Substituted cyclic amine metalloprotease inhibitors

ABSTRACT

The invention provides compounds which are useful as inhibitors of metalloproteases, and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the present invention relates to a compound having a structure according to Formula (I).  
                 
Also disclosed are compounds, pharmaceutical compositions and methods of treating diseases characterized by metalloprotease activity using these compounds or the pharmaceutical compositions containing them.

CROSS REFERENCE

This is a Continuation-in-Part of U.S. application Ser. Nos. 09/888,675 and 09/888,759 filed concurrently on Jun. 25, 2001, which are Divisionals of U.S. application Ser. No. 08/918,317, filed Aug. 26, 1997 which claims priority under Title 35, United States Code 119(e) from Provisional Application Ser. No. 60/024,842, filed Aug. 28, 1996.

TECHNICAL FIELD

This invention is directed to compounds which are useful in treating diseases associated with metalloprotease activity, particularly zinc metalloprotease activity.

BACKGROUND

A number of structurally related metalloproteases [MPs] effect the breakdown of structural proteins. These metalloproteases often act on the intercellular matrix, and thus are involved in tissue breakdown and remodeling. Such proteins are referred to as metalloproteases or MPs. There are several different families of MPs, classified by sequence homology. Several families of known MPs, as well as examples thereof, are disclosed in the art.

These MPs include Matrix-Metallo Proteases [MMPs], zinc metalloproteases, many of the membrane bound metalloproteases, TNF converting enzymes, angiotensin-converting enzymes (ACEs), disintegrins, including ADAMs (See Wolfsberg et al, 131 J. Cell Bio. 275-78 October, 1995), and the enkephalinases. Examples of MPs include human skin fibroblast collagenase, human skin fibroblast gelatinase, human sputum collagenase, aggrecanse and gelatinase, and human stromelysin. Collagenase, stromelysin, aggrecanase and related enzymes are thought to be important in mediating the symptomatology of a number of diseases.

Potential therapeutic indications of MP inhibitors have been discussed in the literature. See for example, U.S. Pat. No. 5,506,242 (Ciba Geigy Corp.); U.S. Pat. No. 5,403,952 (Merck & Co.); PCT published application WO 96/06074 (British Bio Tech Ltd); PCT Publication WO 96/00214 (Ciba Geigy); WO 95/35275 (British Bio Tech Ltd); WO 95/35276 (British Bio Tech Ltd); WO 95/33731 (Hoffman-LaRoche); WO 95/33709 (Hoffman-LaRoche); WO 95/32944 (British Bio Tech Ltd); WO 95/26989 (Merck); WO 9529892 (DuPont Merck); WO 95/24921 (Inst. Opthamology); WO 95/23790 (SmithKline Beecham); WO 95/22966 (Sanbfi Winthrop); WO 95/19965 (Glycomed); WO 95 19956 (British Bio Tech Ltd); WO 95/19957 (British Bio Tech Ltd); WO 95/19961 (British Bio Tech Ltd) WO 95/13289 (Chiroscience Ltd.); WO 95/12603 (Syntex); WO 95/09633 (Florida State Univ); WO 95/09620 (Florida State Univ.); WO 95/04033 (Celltech); WO 94/25434 (Celltech); WO 94/25435 (Celltech); WO 93/14112 (Merck); WO 94/0019 (Glaxo); WO 93/21942 (British Bio Tech Ltd); WO 92/22523 (Res. Corp. Tech. Inc.); WO 94/10990 (British Bio Tech Ltd); WO 93/09090 (Yamanouchi); and British patents GB 2282598 (Merck) and GB 2268934 (British Bio Tech Ltd); Published European Patent Applications EP 95/684240 (Hoffman LaRoche); EP 574758 (Hoffman LaRoche); EP 575844 (Hoffman LaRoche); Published Japanese applications; JP 08053403 (Fujusowa Pharm. Co. Ltd.); JP 7304770 (Kanebo Ltd.); and Bird et al J. Med Chem vol. 37, pp. 158-69 (1994). Examples of potential therapeutic uses of MP inhibitors include rheumatoid arthritis (Mullins, D. E., et al., Biochim. Biophys. Acta. (1983) 695:117-214); osteoarthritis (Henderson, B., et al., Drugs of the Future (1990) 15:495-508); the metastasis of tumor cells (ibid, Broadhurst, M. J., et al., European Patent Application 276,436 (published 1987), Reich, R., et al., 48 Cancer Res. 3307-3312 (1988); and various ulcerations or ulcerative conditions of tissue. For example, ulcerative conditions can result in the cornea as the result of alkali burns or as a result of infection by Pseudomonas aeruginosa, Acanthamoeba, Herpes simplex and vaccinia viruses.

Other examples of conditions characterized by undesired metalloprotease activity include periodontal disease, epidermolysis bullosa, fever, inflammation and scleritis (Cf. DeCicco et al, WO 95 29892 published Nov. 9, 1995).

In view of the involvement of such metalloproteases in a number of disease conditions, attempts have been made to prepare inhibitors to these enzymes. A number of such inhibitors are disclosed in the literature. Examples include U.S. Pat. No. 5,183,900, issued Feb. 2, 1993 to Galardy; U.S. Pat. No. 4,996,358, issued Feb. 26, 1991 to Handa, et al.; U.S. Pat. No. 4,771,038, issued Sep. 13, 1988 to Wolanin, et al.; U.S. Pat. No. 4,743,587, issued May 10, 1988 to Dickens, et al., European Patent Publication Number 575,844, published Dec. 29, 1993 by Broadhurst, et al.; International Patent Publication No. WO 93/09090, published May 13, 1993 by Isomura, et al.; World Patent Publication 92/17460, published Oct. 15, 1992 by Markwell et al.; and European Patent Publication Number 498,665, published Aug. 12, 1992 by Beckett, et al.

Though a variety of inhibitors have been prepared, there is a continuing need for potent matrix metalloprotease inhibitors useful in treating such diseases. It would be advantageous to inhibit these metalloproteases as a method of treating diseases related to unwanted metalloprotease activity. Though a variety of inhibitors have been prepared, there is a continuing need for potent metalloprotease inhibitors useful in treating such diseases.

OBJECTS OF THE INVENTION

It is an object of the inventionto provide potent inhibitors of metalloproteases.

It is a further object of the invention to provide pharmaceutical compositions comprising such inhibitors.

It is also an object of the invention to provide a method of treatment for metalloprotease related maladies.

SUMMARY OF THE INVENTION

The invention provides compounds which are useful as inhibitors of metalloproteases, and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the present invention relates to a compound having a structure according to Formula (I)

wherein

-   -   Ar is alkyl, heteroalkyl, aryl or heteroaryl, substituted or         unsubstituted;     -   R₁ is OH, alkoxy, NHOR₂, where R₂ is hydrogen or alkyl;     -   W is one or more of hydrogen, lower alkyl or an alkylene bridge;     -   Y is independently one or more of hydroxy, SR₃, SOR₄, SO₂R₅,         alkoxy, amino, wherein amino is of formula NR₆,R₇, wherein R₆         and R₇ are independently chosen from hydrogen, alkyl,         heteroalkyl, heteroaryl, aryl, OR₃, SO₂R₈, COR₉, CSR₁₀,         PO(R₁₁)₂; and     -   R₃ is hydrogen, alkyl, aryl, heteroaryl;     -   R₄ is alkyl, aryl, heteroaryl;     -   R₈ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,         dialkylamino, arylamino, diarylamino and alkylarylamino;     -   R₉ is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl,         heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino,         arylamino and alkylarylamino;     -   R₁₀ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,         dialkylamino, arylamino, diarylamino and alkylarylamino;     -   R₁₁ is alkyl, aryl, heteroaryl, heteroalkyl;     -   Z is hydrogen, hydroxy, alkyl, alkylene or heteroalkylene;     -   n is 1-3.

This structure also includes an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.

These compounds have the ability to inhibit at least one mammalian matrix metalloprotease. Accordingly, in other aspects, the invention is directed to pharmaceutical compositions containing the compounds of Formula (I), and to methods of treating diseases characterized by metalloprotease activity using these compounds or the pharmaceutical compositions containing them.

Applicants have found that compounds of Formula (I) are potent inhibitors of metalloproteases. The compounds of the present invention therefore are useful for the treatment of conditions and diseases which are characterized by unwanted activity by the class of proteins which destroy structural proteins.

Metalloproteases active at a particularly undesired location (e.g., an organ or certain types of cells) can be targeted by conjugating the compounds of the invention to a targeting ligand specific for a marker at that location such as an antibody or fragment thereof or a receptor ligand. Conjugation methods are known in the art.

The invention is also directed to various other processes which take advantage of the unique properties of these compounds. Thus, in another aspect, the invention is directed to the compounds of Formula (I) conjugated to solid supports. These conjugates can be used as affinity reagents for the purification of a desired metalloprotease.

In another aspect, the invention is directed to the compounds of Formula (I) conjugated to label. As the compounds of the invention bind to at least one metalloprotease, the label can be used to detect the presence of relatively high levels of metalloprotease in vivo or in vitro cell culture.

In addition, the compounds of Formula (I) can be conjugated to carriers which permit the use of these compounds in immunization protocols to prepare antibodies specifically immunoreactive with the compounds of the invention. Typical conjugation methods are known in the art. These antibodies are then useful both in therapy and in monitoring the dosage of the inhibitors.

DETAILED DESCRIPTION

The compounds of the present invention are inhibitors of mammalian metalloproteases. Preferably, the compounds are those of Formula (I) or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.

Definitions and Usage of Terms:

The following is a list of definitions for terms used herein:

“Acyl” or “carbonyl” is described as a radical which could be formed by removal of the hydroxy from a carboxylic acid (i.e., R—C(═O)—). Preferred acyl groups include (for example) acetyl, formyl, and propionyl.

“Acyloxy” is an oxy radical having an acyl substituent (i.e., —O-acyl); for example, —O—C(═O)-alkyl.

“Alkoxyacyl” is an acyl radical (—C(═O)—) having an alkoxy subtituent (i.e., —O—R), for example, —C(═O)—O-alkyl. This radical can be referred to as an ester.

“Acylamino” is an amino radical having an acyl substituent (i.e., —N-acyl); for example, —NH—C(═O)-alkyl.

“Alkenyl” is an unsubstituted or substituted hydrocarbon chain radical having 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; more preferably from 2 to 8; except where indicated. Alkenyl substituents have at least one olefinic double bond (including, for example, vinyl, allyl and butenyl).

“Alkynyl” is an unsubstituted or substituted hydrocarbon chain radical having 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; more preferably from 2 to 8; except where indicated. The chain has at least one carbon-carbon triple bond.

“Alkoxy” is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e., —O-alkyl or —O-alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy.

“Alkoxyalkyl” is an unsubstituted or substituted alkyl moiety substituted with an alkoxy moiety (i.e., -alkyl—O-alkyl). Preferred is where the alkyl has 1 to 6 carbon atoms (more preferably 1 to 3 carbon atoms), and the alkyoxy has 1 to 6 carbon atoms (more preferably 1 to 3 carbon atoms).

“Alkyl” is an unsubstituted or substituted saturated hydrocarbon chain radical having 1 to 15 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 1 to 4; except where indicated. Preferred alkyl groups include (for example) substituted or unsubstituted methyl, ethyl, propyl, isopropyl, and butyl.

Alkylene refers to an alkyl, alkenyl or alkynyl which is diradical, rather than a radical. “Hetero alkylene” is likewise defined as a (diradical) alkylene having a heteroatom in its chain. hence an “alkylene bridge” is a hydrocarbon diradical that attaches to two different carbons (hence making a bicyclic structure), prefered alkylene bridges include methylene, ethylene and propylene.

“Alkylamino” is an amino radical having one (secondary amine) or two (tertiary amine) alkyl substituents (i.e., —N-alkyl). For example, methylamino (—NHCH₃), dimethylamino (—N(CH₃)₂), methylethylamino (—N(CH₃)CH₂CH₃).

“Aminoacyl” is acyl radical having an amino substituent (i.e., —C(═O)—N); for example, —C(═O)—NH₂. The amino group of the aminoacyl moiety may be unsubstituted (i.e., primary amine) or may be substituted with one (secondary amine) or two (i.e., tertiary amine) alkyl groups.

“Aryl” is an aromatic carbocyclic ring radical. Preferred aryl groups include (for example) phenyl, tolyl, xylyl, cumenyl and naphthyl.

“Arylalkyl” is an alkyl radical substituted with an aryl group. Preferred arylalkyl groups include benzyl, phenylethyl, and phenylpropyl.

“Arylalkylamino” is an amine radical substituted with an arylalkyl group (e.g., —NH-benzyl).

“Arylamino” is an amine radical substituted with an aryl group (i.e., —NH-aryl).

“Aryloxy” is an oxygen radical having an aryl substituent (i.e., —O-aryl).

“Carbocyclic ring” is an unsubstituted or substituted, saturated, unsaturated or aromatic, hydrocarbon ring radical. Carbocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic carbocyclic rings generally contain 4 to 9 atoms, preferably 4 to 7 atoms. Polycyclic carbocyclic rings contain 7 to 17 atoms, preferably from 7 to 12 atoms. Preferred polycyclic systems comprise 4-, 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings.

“Carbocycle-alkyl” is an unsubstituted or substituted alkyl radical substituted with a carbocyclic ring. Unless otherwise specified, the carbocyclic ring is preferably an aryl or cycloalkyl; more preferably an aryl. Preferred carbocycle-alkyl groups include benzyl, phenylethyl and phenylpropyl.

“Carbocycle-heteroalkyl” is an unsubstituted or substituted heteroalkyl radical substituted with a carbocyclic ring. Unless otherwise specified, the carbocyclic ring is preferably an aryl or cycloalkyl; more preferably an aryl. The heteroalkyl is preferably 2-oxa-propyl, 2-oxa-ethyl, 2-thia-propyl, or 2-thia-ethyl.

“Carboxyalkyl” is an unsubstituted or substituted alkyl radical substituted with with a carboxy (—C(═O)OH) moiety. For example, —CH₂—C(═O)OH.

“Cycloalkyl” is a saturated carbocyclic ring radical. Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl.

“Cycloheteroalkyl” is a saturated heterocyclic ring. Preferred cycloheteroalkyl groups include (for example) morpholinyl, piperadinyl, and piperazinyl.

“Fused rings” are rings that are superimposed together such that they share two ring atoms. A given ring may be fused to more than one other ring. Fused rings are contemplated in heteroaryl, aryl and heterocycle radicals or the like.

“Heterocycle-alkyl” is an alkyl radical substituted with a heterocyclic ring. The heterocyclic ring is preferably an heteroaryl or cycloheteroalkyl; more preferably an heteroaryl. Preferred heterocycle alkyl include C₁-C₄ alkyl having preferred heteroaryl appended to them. More preferred is, for example, pyridyl alkyl, and the like.

“Heterocycle-heteroalkyl” is an unsubstituted or substituted heteroalkyl radical substituted with a heterocyclic ring. The heterocyclic ring is preferably an aryl or cycloheteroalkyl; more preferably an aryl.

“Heteroatom” is a nitrogen, sulfur or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms.

“Heteroalkenyl” is an unsubstituted or substituted unsaturated chain radical having 3 to 8 members comprising carbon atoms and one or two heteroatoms. The chain has at least one carbon-carbon double bond.

“Heteroalkyl” is an unsubstituted or substituted saturated chain radical having 2 to 8 comprising carbon atoms and one or two heteroatoms.

“Heterocyclic ring” is an unsubstituted or substituted, saturated, unsaturated or aromatic ring radical comprised of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic heterocyclic rings contain 3 to 9 atoms, preferably 4 to 7 atoms. Polycyclic rings contain 7 to 17 atoms, preferably from 7 to 13 atoms.

“Heteroaryl” is an aromatic heterocyclic ring, either monocyclic or bicyclic radical. Preferred heteroaryl groups include (for example) thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, and tetrazolyl, benzo thiazolyl, benzofuryl, indolyl and the like.

“Halo”, “halogen”, or “halide” includes chloro, bromo, fluoro or iodo, preferably chloro and fluoro.

Also, as referred to herein, a “lower” hydrocarbon moiety (e.g., “lower” alkyl) is a hydrocarbon chain comprised of 1 to 6, preferably from 1 to 4, carbon atoms.

A “pharmaceutically-acceptable salt” is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published Sep. 11, 1987 (incorporated by reference herein). Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include the halides (such as chloride salts). Such salts are well understood bythe skilled artisan, and the skilled artisan is able to prepare any number fo salts given the knowledge in the art. Furthermore, it is recognized that the skilled artisan may prefer one salt over another for reasons of solubility, stability, formulation ease and the like. Determination and optimization of of such salts is within the purview of the skilled artisan's practice.

“Biohydrolyzable amides” are amides of a metalloprotease inhibitor that do not interfere with the inhibitory activity of the compound, or that are readily converted in vivo by an animal, preferably a mammal, more preferably a human subject to yield an active metalloprotease inhibitor.

A “biohydrolyzable hydroxy imide” is an imide of a Formula (I) compound that does not interfere with the metalloprotease inhibitory activity of these compounds, or that is readily converted in vivo by an animal, preferably a mammal, more preferably a human subject to yield an active Formula (I) compound.

A “biohydrolyzable ester” refers to an ester of a Formula (I) compound that does not interfere with the metalloprotease inhibitory activity of these compounds or that is readily converted by an animal to yield an active Formula (I) compound.

A “solvate” is a complex formed by the combination of a solute (e.g., a metalloprotease inhibitor) and a solvent (e.g., water). See J. Honig et al., The Van Nostrand Chemist's Dictionary, p. 650 (1953). Pharmaceutically-acceptable solvents used according to this invention include those that do not interfere with the biological activity of the metalloprotease inhibitor (e.g., water, ethanol, acetic acid, N,N-dimethylformamide and others known or readily determined by the skilled artisan).

“Optical isomer”, “stereoisomer”, “diastereomer” as referred to herein have the standard art recognized meanings (Cf., Hawley's Condensed Chemical Dictionary, 11th Ed.).

The illustration of specific protected forms and other derivatives of the Formula (I) compounds is not intended to be limiting. The application of other useful protecting groups, salt forms, etc. is within the ability of the skilled artisan.

As defined above and as used herein, substituent groups may themselves be substituted. Such substitution may be with one or more substituents. Such substituents include those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorporated by reference herein. Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxyaceyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.

As used herein, “mammalian metalloprotease” refers to the proteases disclosed in the

“Background” of this application. Prefered “mammalian metalloproteases” include any metal-containing (preferably zinc-containing) enzyme found in animal, preferably mamalian sources capable of catalyzing the breakdown of collagen, gelatin or proteoglycan under suitable assay conditions. Appropriate assay conditions can be found, for example, in U.S. Pat. No. 4,743,587, which references the procedure of Cawston, et al., Anal. Biochem. (1979) 99:340-345, use of a synthetic substrate is described by Weingarten, H., et al., Biochem. Biophy. Res. Comm. (1984) 139:1184-1187. Any standard method for analyzing the breakdown of these structural proteins can, of course, be used. More prefered metalloprotease enzymes are zinc-containing proteases which are similar in structure to, for example, human stromelysin or skin fibroblast collagenase. The ability of candidate compounds to inhibit metalloprotease activity can, of course, be tested in the assays described above. Isolated metalloprotease enzymes can be used to confirm the inhibiting activity of the invention compounds, or crude extracts which contain the range of enzymes capable of tissue breakdown can be used.

Compounds:

Compounds of the invention are described in the Summary of the Invention, more preferred compounds of Formula (I) include,

wherein

-   -   Ar is aryl or heteroaryl, substituted or unsubstituted;     -   R₁ is OH, alkoxy, NHOR₂, where R₂ is hydrogen or alkyl;     -   W is one or more of hydrogen, lower alkyl;     -   Y is independently one or more of hydroxy, SR₃, SOR₄, SO₂R₅,         alkoxy, amino, wherein amino is of formula NR₆,R₇, wherein R₆         and R₇ are independently chosen from hydrogen, alkyl,         heteroalkyl, heteroaryl, aryl, OR₃, SO₂R₈, COR₉, CSR₁₀,         PO(R₁₁)₂; and     -   R₃ is hydrogen, alkyl, aryl, heteroaryl;     -   R₄ is alkyl, aryl, heteroaryl;     -   R₈ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,         dialkylamino, arylamino, diarylamino and alkylarylamino;     -   R₉ is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl,         heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino,         arylamino and alkylarylamino;     -   R₁₀ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,         dialkylamino, arylamino, diarylamino and alkylarylamino;     -   R₁₁ is alkyl, aryl, heteroaryl, heteroalkyl;     -   Z is hydrogen;     -   n is 1-3.

There may be one or more W, Y and Z moeities on the molecule of the invention. Preferably there are five or less subsituuents chosen from W, Y and Z which are not hydrogen. Y and Z moieties may appear on the same carbon, i.e., geminal in relation to each other.

Where Z is heteroalkylene, it is prefered that heteroatoms adjacent to the parent ring structure, more preferably such heteroalkyls have 2 to 4 members. Perferred heteroatoms are divalent.

Preferred Ar include aryl and alkyl moieties. When Ar is aryl, it includes heterocyclic and carbocyclic aryl, either monocyclic or polyciclic, preferably monocyclic aryl, more preferably phenyl; When Ar is alkyl, it is preferably C₁ to C₁₈ alkyl, more preferably C₂ to C₈ alkyl or heteroalkyl. Ar can be substituted or unsubstituted.

W is preferably a C₁ to C₄ alkyl or C₁ to C₄ alkylene bridge. When W is an alkylene bridge, it is preferably methylene, ethylene or propylene, more preferably methylene. When W is alkyl it is preferably methyl or ethyl, more preferably methyl.

The variable “n” alters the size of the nitrogen containing ring, more preferred ring sizes are 5 and 6 membered rings.

Compound Preparation:

The hydroxamic compounds of Formula (I) can be prepared using a variety of procedures.

The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available as a starting material. General schemes and representative examples of the preparation of compounds of the invention follow.

In the following scheme W and Z are omitted for clarity. The skilled artisan will appreciate that Z may be added using similar methodologies or those known in the art. W may be added by art recognized methodologies as well. For compounds where Y is not adjacent to the ring nitrogen, a preferred method of making the compounds is;

Where R is a derivatizable group or can be manipulated or substituted, such compounds are known or are prepared by known methods. For example, when R is OH, and n is 1, hydroxyproline (A) is converted to its analogous sultamester and the hydroxyl is then manipulated to give (B) during is this or a subsequent step Y and Z can be added or altered, followed by treatment with hydroxyl amine under basic conditions to give (C).

R′ may be a protecting group, a free acid or any moiety the skilled artisan prefers, provided that ultimately it provides the compounds of the invention.

A variety of compounds can be generated in a similar fashion, using the guidance of the scheme above.

It is recognized that it is preferable to use a protecting group for any reactive functionality such as a carboxyl, hydroxyl and the like, during the formation of the sultamester. This is standard practice, well within the normal practice of the skilled artisan.

In the above schemes, where R is alkoxy or alkylthio, the corresponding hydroxy or thiol compounds are derived from the final compounds by using a standard dealkylating procedure (Bhatt, et al., “Cleavage of Ethers”, Synthesis, 1983, pp. 249-281).

These steps may be varied to increase yield of desired product. The skilled artisan will recognize the judicious choice of reactants, solvents, and temperatures is an important component in any successful synthesis. Determination of optimal conditions, etc. is routine. Thus the skilled artisan can make a variety of compounds using the guidance of the scheme above.

It is recognized that the skilled artisan in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction; that is, it is well within the scope and practice of the skilled artisan to carry out such manipulations. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations of hydroxyls and the like, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. Examples of these manipulations are discussed in standard texts such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2) and other art that the skilled artisan is aware of.

The skilled artisan will readily appreciate that certain reactions are best carried out when other potentially reactive functionality onthe molecule is masked or protected, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene, Protecting Groups in Organic Svnthesis. Of course, amino acids used as starting materials with reactive side chains are preferably blocked to prevent undesired side reactions.

The compounds of the invention may have one or more chiral centers. As a result, one may selectively prepare one optical isomer, including diastereomer and enantiomer, over another, for example by chiral starting materials, catalysts or solvents, or may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers may be separated using known methods, such as chiral salts, chiral chromatography and the like.

In addition, it is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.

Methods of Use

Metalloproteases (MPs) found in the body operate, in part, by breaking down the extracellular matrix, which comprises extracellular proteins and glycoproteins. These proteins and glycoproteins play an important role in maintaining the size, shape, structure and stability of tissue in the body. Inhibitors of metalloproteases are useful in treating diseases caused, at least in part, by breakdown of such proteins. It is known that MPs are intimately involved in tissue remodeling. As a result of this activity they have been said to be active in many disorders involving either the:

-   -   breakdown of tissues; including degenerative diseases, such as         arthritis, multiple sclerosis and the like; metastasis or         mobility of tissues in the body:     -   the remodeling of tissues, including fibrotic disease, scarring,         benign hyperplasia, and the like.         The compounds of the present invention treat disorders, diseases         and/or unwanted conditions which are characterized by unwanted         or elevated activity by that class of proteases. For example the         compounds can be used to inhibit proteases which:     -   destroy structural proteins (i.e. the proteins that maintain         tissue stability and structure);     -   interfere in inter/intracellular signaling, including those         implicated in cytokine up-regulation, and/or cytokine processing         and/or inflammation, tissue degradation and other maladies         [Mohler KM, et al, Nature 370 (1994) 218-220, Gearing AJH, et         al, Nature 370 (1994) 555-557 McGeehan GM, et al, Nature         370 (1994) 558-561], and/or     -   facilitate processes which are undesired in the subject being         treated, for example, the processes of sperm maturation, egg         fertilization and the like.

The term “treatment” is used herein to mean that, at a minimum, administration of a compound of the present invention that mitigates a “MP related disorder or disease” in a mammalian subject, preferably in humans. Thus, the term “treatment” includes: preventing an UP related disorder from occurring in a mammal, particularly when the mammal is predisposed to acquiring the MP related disorder, but has not yet been diagnosed with the disease; inhibiting the MP related disorder; and/or alleviating or reversing the MP related disorder. Insofar as the methods of the present invention are directed to preventing an MP related disorder, it is understood that the term “prevent” does not require that the MP related disorder be completely thwarted. (See Webster's Ninth Collegiate Dictionary.) Rather, as used herein, the term “preventing” refers to the ability of the skilled artisan to identify a population that is susceptible to MP related disorder, such that administration of the compounds of the present invention may occur prior to the onset of the symptoms of the MP related disorder. The population that is at risk of a MP related disorder, for example as heart disease, are those who have a genetic predisposition to heart disease as indicated by family history of the disease. Other risk factors include obesity, stress, and/or a diet high in atherogenic lipids.

Thus, the patient population is identifiable and could receive the administration of a composition of the present invention before progression of the disease. Thus, progression of the MP related disorder in such individuals would be “prevented.”

As used herein, a “MP related disorder” or “a MP related disease” is one that involves unwanted or elevated MP activity in the biological manifestation of the disease or disorder; in the biological cascade leading to the disorder; or as a symptom of the disorder. This “involvement” of the MP includes;

-   -   The unwanted or elevated MP activity as a “cause” of the         disorder or biological manifestation, whether the activity was         elevated genetically, by infection, by autoimmunity, trauma,         biomechanical causes, lifestyle [e.g. obesity] or by some other         cause;     -   The MP as part of the observable manifestation of the disease or         disorder. That is, the disease or disorder is measurable in         terms of the increased MP activity, or from a clinical         standpoint, unwanted or elevated MP levels indicate the disease.         MPs need not be the “hallmark” of the disease or disorder;     -   The unwanted or elevated MP activity is part of the biochemical         or cellular cascade that results or relates to the disease or         disorder. In this respect, inhibition of the MP activity         interrupts the cascade, and thus controls the disease.

Advantageously, many MPs are not distributed evenly throughout the body. Thus the distribution of MPs expressed in various tissues are often specific to those tissues. For example, the distribution of metalloproteases implicated in the breakdown of tissues in the joints, is not the same as the distribution of metalloproteases found in other tissues. Thus, though not essential for activity or to efficacy, certain disorders preferably are treated with compounds that act on specific MPs found in the affected tissues or regions of the body. For example, a compound which displays a higher degree of affinity and inhibition for a MP found in the joints (e.g. chondrocytes) would be preferred for treatment of disease found there than other compounds which are less specific.

In addition, certain inhibitors are more bioavialable to certain tissues than others, and this judicious choice of inhibitor, with the selectivity described above provides for specific treatment of the disorder, disease or unwanted condition. For example, compounds of this invention vary in their ability to penetrate into the central nervous system. Thus compounds may be selected to produce effects mediated through MPs found specifically outside the central nervous system.

Determination of the specificity of a MP inhibitor of a certain M is within the skill of the artisan in that field. Appropriate assay conditions can be found in the literature. Specifically assays are known for stromelysin and collagenase. For example, U.S. Pat. No. 4,743,587 references the procedure of Cawston, et al., Anal Biochem (1979) 99:340-345. The use of a synthetic substrate in an assay is described by Weingarten, H., et al., Biochem Biophy Res Comm (1984) 139:1184-1187. Any standard method for analyzing the breakdown of structural proteins by MPs can, of course, be used. The ability of compounds of the invention to inhibit metalloprotease activity can, of course, be tested in the assays found in the literature, or variations thereof. Isolated metalloprotease enzymes can be used to confirm the inhibiting activity of the invention compounds, or crude extracts which contain the range of enzymes capable of tissue breakdown can be used.

As a result of the MP inhibitory effect of the compounds of the invention, the compounds of the invention are also useful in treating the following disorders by virtue of their metalloprotease activity.

The compounds of this invention are also useful for the prophylactic or acute treatment. They are administered in any way the skilled artisan in the fields of medicine or pharmacology would desire. It is immediately apparent to the skilled artisan that preferred routes of administration will depend upon the disease state being treated, and the dosage form chosen. Preferred routes for systemic administration include administration perorally or parenterally.

However, the skilled artisan will readily appreciate the advantage of administering the MP inhibitor directly to the affected area for many disorders. For example, it may be advantageous to administer MP inhibitors directly to the area of the disease or condition as in area affected by surgical trauma (e. g., angioplasty), area affected by scarring or burn (e.g., topical to the skin),

Because the remodeling of bone involves MPs, the compounds of the invention are useful in preventing prosthesis loosening. It is known in the art that over time prostheses loosen, become painful, and may result in further bone injury, thus demanding replacement. The need for replacement of such prostheses includes those such as in, joint replacements (for example hip, knee and shoulder replacements), dental prosthesis, including dentures, bridges and prosthesis secured to the maxilla and/or mandible.

MPs are also active in remodeling of the cardiovascular system (for example, in congestive heart failure). It has been suggested that one of the reasons angioplasty has a higher than expected long term failure rate (reclosure over time) is that MP activity is not desired or is elevated in response to what may be recognized by the body as “injury” to the basement membrane of the vessel. Thus regulation of MP activity in indications such as dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, angioplasty restenosis and aortic aneurysm may increase long term success of any other treatment, or may be a treatment in itself.

In one aspect of the present invention, the compounds of Formula I of the present invention may be effective in preventing or treating myocardial infarction (hereinafter “MI”). MI, also known as a “heart attack” or “heart failure,” is a condition caused by partial or complete occlusion of one or more of the coronary arteries, usually due to rupture of an atherosclerotic plaque. The occlusion of the coronary artery results in cardiac ischemia. MMPs are implicated in artherosclerotic plaque rupture. See e.g., Galis, Z. S., et al., J. Clin. Invest. 1994;94:2493-503; Lee, R. T., et al., Arterioscler.Thromb.Vasc.Biol. 1996;16:1070-73; Schonbeck, U. et al., Circulation Research 1997; 81(3), 448-454. Libby, P. et al., Circ. 1995;91:2844-50.

In another aspect of the invention, the compounds of the present invention may be effective in preventing or treating progressive ventricular dilation after a MI, the major contributing factor to the development of post-MI chronic heart failure (hereinafter “CHF”). Thus, in yet still another aspect of the invention, the compounds of the present invention may be effective in preventing or treating the development of post-MI chronic heart failure.

It is widely recognized that important structural changes occur within the ventricular myocardium following MI that results in alterations in LV geometry and function. These structural alterations occur in the infarct itself, in the border zone of the MI, and in regions remote from the MI that collectively result in progressive ventricular dilation and pump dysfunction. The most notable feature of this remodeling process is the region of the original MI appears to enlarge with thinning of the ventricular myocardial wall. This type of remodeling following the initial injury and healing process from an MI has been termed “infarct expansion.” A significant body of work suggests that treatment of acute myocardial infarction with an MMP inhibitor will limit the unfavorable dilation of the heart that occurs early after such an event and therefore improve outcomes by preventing long-term sequelae, such as the development of chronic heart failure. See, e.g., Spinale, F. G. et al., Circulation Research 82:482-495 (1998); McElmurray, J. H. I. et al., J. Pharmacol. Exp. Ther. 291:799-811 (1999); Thomas, C. V. et al., Circulation 97:1708-1715 (1998); Spinale, F. G. et al. Circ. 102:1944-49 (2000); Peterson, J. T. et al., Cardiovasc.Res., 46(2):307-15 (2000); Rohde, et al., Circ., 99:3063-70 (1999); Lindsey, M. L. et al., Circ. 105:753-58 (2002); Brinsa, T. A. et al., J. Cardiac Failure, 7 Suppl. 2:24 (2001); Mukherjee, R. et al., J. Cardiac Failure;7 Suppl 2:7 (2001).

A suitable MI cardiac pharmacological model is described in Mukherjee, R. et al., J. Cardiac Failure;7 Suppl 2:7 (2001). Briefly, pigs are prepared for the induction of myocardial infarction by implantation of an occlusion device on the circumflex coronary artery, and radiopaque markers are placed in the region destined to be infarcted to measure infarct expansion (see below). Measurements of left ventricular (hereinafter “LV”) volumes and distances between marker beads are made prior to and at various times after the induction of MI induced by activating the occlusion device. The effects of selective MMP inhibition may be studied in a pig model of MI induced by ligation of the circumflex coronary artery. Animals are assigned to one of the following treatment groups: (1) 1 or 10 mg/kg three times a day of a compound of Formula (I) by oral administration starting 3 days prior to myocardial infarction; (2) 10 mg/kg three times a day of said compound by oral administration starting 3 days after MI; (3) MI with no active treatment; or (4) no myocardial infarction or drug treatment. At 10 days post-MI, LV end-diastolic volume (hereinafter “LVEDV”) is measured by ventriculography. LVEDV is increased in all MI groups. An attenuated increase in LVEDV by a compound of Formula (I) indicates that the compound may be effective in the prevention or treatment of progressive ventricular dilation, and thus the subsequent development of CHF.

In skin care, MPs are implicated in the remodeling or “turnover” of skin. As a result, the regulation of MPs improves treatment of skin conditions including but not limited to, wrinkle repair, regulation and prevention and repair of ultraviolet induced skin damage. Such a treatment includes prophylactic treatment or treatment before the physiological manifestations are obvious. For example, the MU may be applied as a pre-exposure treatment to prevent ultaviolet damage and/or during or after exposure to prevent or minimize post-exposure damage. In addition, MPs are implicated in skin disorders and diseases related to abnormal tissues that result from abnormal turnover, which includes metalloprotease activity, such as epidermolysis bullosa, psoriasis, scleroderma and atopic dermatitis. The compounds of the invention are also useful for treating the consequences of “normal” injury to the skin including scarring or “contraction” of tissue, for example, following burns. MP inhibition is also useful in surgical procedures involving the skin for prevention of scarring, and promotion of normal tissue growth including in such applications as limb reattachment and refractory surgery (whether by laser or incision).

In addition, MPs are related to disorders involving irregular remodeling of other tissues, such as bone, for example, in otosclerosis and/or osteoporosis, or for specific organs, such as in liver cirrhosis and fibrotic lung disease. Similarly in diseases such as multiple sclerosis, MBs may be involved in the irregular modeling of blood brain barrier and/or myelin sheaths of nervous tissue. Thus regulating MP activity may be used as a strategy in treating, preventing, and controlling such diseases.

MPs are also thought to be involved in many infections, including cytomegalovirus; [CMV] retinitis; HIV, and the resulting syndrome, AIDS.

MPs may also be involved in extra vascularization where surrounding tissue needs to be broken down to allow new blood vessels such as in angiofibroma and hemangioma.

Since MPs break down the extracellular matrix, it is contemplated that inhibitors of these enzymes can be used as birth control agents, for example in preventing ovulation, in preventing penetration of the sperm into and through the extracellular milieu of the ovum, implantation of the fertilized ovum and in preventing sperm maturation.

In addition they are also contemplated to be useful in preventing or stopping premature labor and delivery.

Since MPs are implicated in the inflammatory response, and in the processing of cytokines the compounds are also useful as anti-inflammatories, for use in disease where inflammation is prevalent including, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis, diverticulitis, asthma or related lung disease, rheumatoid arthritis, gout and Reiter's Syndrome.

Where autoimmunity is the cause of the disorder, the immune response often triggers MP and cytokine activity. Regulation of MPs in treating such autoimmune disorders is a useful treatment strategy. Thus MP inhibitors can be used for treating disorders including, lupus erythmatosis, ankylosing spondylitis, and autoimmune keratitis. Sometimes the side effects of autoimmune therapy result in exacerbation of other conditions mediated by MPs, here MP inhibitor therapy is effective as well, for example, in autoimmune-therapy-induced fibrosis.

In addition, other fibrotic diseases lend themselves to this type of therapy, including pulmonary disease, bronchitis, emphysema, cystic fibrosis, acute respiratory distress syndrome (especially the acute phase response).

Where MPs are implicated in the undesired breakdown of tissue by exogenous agents, these can be treated with MP inhibitors. For example, they are effective as rattle snake bite antidote, as anti-vessicants, in treating allergic inflammation, septicemia and shock. In addition, they are useful as antiparasitics (e.g., in malaria) and antiinfectives. For example, they are thought to be useful in treating or preventing viral infection, including infection which would result in herpes, “cold” (e.g., rhinoviral infection), meningitis, hepatitis, HIV infection and AIDS.

MP inhibitors are also thought to be useful in treating Alzheimer's disease, amyotrophic lateral sclerosis (ALS), muscular dystrophy, complications resulting from or arising out of diabetes, especially those involving loss of tissue viability, coagulation, Graft vs. Host disease, leukemia, cachexia, anorexia, proteinuria, and perhaps regulation of hair growth.

For some diseases, conditions or disorders MP inhibition is contemplated to be a preferred method of treatment. Such diseases, conditions or disorders include, arthritis (including osteoarthritis and rheumitoid arthritis), cancer (especially the prevention or arrest of tumor growth and metastasis), ocular disorders (especially corneal ulceration, lack of corneal healing, macular degeneration, and pterygium), and gum disease (especially periodontal disease, and gingivitis)

Compounds preferred for, but not limited to, the treatment of arthritis (including osteoarthritis and rheumatoid arthritis) are those compounds that are selective for the matrix metalloproteases and the disintegrin metalloproteases.

Compounds preferred for, but not limited to, the treatment of cancer (especially the prevention or arrest of tumor growth and metastasis) are those compounds that preferentially inhibit gelatinases or type IV collagenases.

Compounds preferred for, but not limited to, the treatment of ocular disorders (especially is corneal ulceration, lack of corneal healing, macular degeneration, and pterygium) are those compounds that broadly inhibit metalloproteases. Preferably these compounds are administered topically, more preferably as a drop or gel.

Compounds preferred for, but not limited to, the treatment of gum disease (especially periodontal disease, and gingivitis) are those compounds that preferentially inhibit collagenases.

Compositions:

The compositions of the invention comprise:

(a) a safe and effective amount of a compound of Formula (I); and

(b) a pharmaceutically-acceptable carrier.

As discussed above, numerous diseases are known to be mediated by excess or undesired metalloprotease activity. These include tumor metastasis, osteoarthritis, rheumatoid arthritis, skin inflammation, ulcerations, particularly of the cornea, reaction to infection, periodontitis and the like. Thus, the compounds of the invention are useful in therapy with regard to conditions involving this unwanted activity.

The invention compounds can therefore be formulated into pharmaceutical compositions for use in treatment or prophylaxis of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., latest edition.

A “safe and effective amount” of a Formula (I) compound is an amount that is effective, to inhibit metalloproteases at the site(s) of activity, in an animal, preferably a mammal, more preferably a human subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific “safe and effective amount” will, obviously, vary with such actors as the particular condition being treated, the physical condition of the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, the carrier employed, the solubility of the Formula (I) compound therein, and the dosage regimen desired for the composition.

In addition to the subject compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier. The term “pharmaceutically-acceptable carrier”, as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to an animal, preferably a mammal, more preferably a human. The term “compatible”, as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal, preferably a mammal, more preferably a human being treated.

Some examples of substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the Tweens”; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.

If the subject compound is to be injected, the preferred pharmaceutically-acceptable carrier is sterile, physiological saline, with blood-compatible suspending agent, the pH of which has been adjusted to about 7.4.

In particular, pharmaceutically-acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically-acceptable carrier, in compositions for parenteral administration, comprises at least about 90% by weight of the total composition.

The compositions of this invention are preferably provided in unit dosage form. As used herein, a “unit dosage form” is a composition of this invention containing an amount of a Formula (I) compound that is suitable for administration to an animal, preferably a mammal, more preferably a human subject, in a single dose, according to good medical practice. These compositions preferably contain from about 5 mg (milligrams) to about 1000 mg, more preferably from about 10 mg to about 500 mg, more preferably from about 10 mg to about 300 mg, of a Formula (I) compound.

The compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the Formula (I) compound. The amount of carrier employed in conjunction with the Formula (I) compound is sufficient to provide a practical quantity of material for administration per unit dose of the Formula (I) compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).

In addition to the subject compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier. The term “pharmaceutically-acceptable carrier”, as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to an animal, preferably a mammal, more preferably a human. The term “compatible”, as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal, preferably a mammal, more preferably a human being treated.

Some examples of substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the Tweens”; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.

If the subject compound is to be injected, the preferred pharmaceutically-acceptable carrier is sterile, physiological saline, with blood-compatible suspending agent, the pH of which has been adjusted to about 7.4.

Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of the Formula (1) compound. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

The pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration are well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations-like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, Avicel” RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.

Compositions of the subject invention may optionally include other drug actives.

Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

The compositions of this invention can also be administered topically to a subject, e.g., by the direct laying on or spreading of the composition on the epidermal or epithelial tissue of the subject, or transdermally via a “patch”. Such compositions include, for example, lotions, creams, solutions, gels and solids. These topical compositions preferably comprise a safe and effective amount, usually at least about 0.1%, and preferably from about 1% to about 5%, of the Formula (I) compound. Suitable carriers for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water. Generally, the carrier is organic in nature and capable of having dispersed or dissolved therein the Formula (I) compound. The carrier may include pharmaceutically-acceptable emolients, emulsifiers, thickening agents, solvents and the like.

Methods of Administration:

This invention also provides methods of treating or preventing disorders associated with excess or undesired metalloprotease activity in a human or other animal subject, by administering a safe and effective amount of a Formula (I) compound to said subject. As used herein, a “disorder associated with excess or undesired metalloprotease activity” is any disorder characterized by degradation of matrix proteins. The methods of the invention are useful in treating disorders described above.

The Formula (I) compounds and compositions of this invention can be administered topically or systemically. Systemic application includes any method of introducing Formula (I) compound into the tissues of the body, e.g., intra-articular (especially in treatment of rheumatoid arthritis), intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oral administration. The Formula (I) compounds of the present invention are preferably administered orally.

The specific dosage of inhibitor to be administered, as well as the duration of treatment, and whether the treatment is topical or systemic are interdependent. The dosage and treatment regimen will also depend upon such factors as the specific Formula (I) compound used, the treatment indication, the ability of the Formula (1) compound to reach minimum inhibitory concentrations at the site of the metalloprotease to be inhibited, the personal attributes of the subject (such as weight), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment.

Typically, for a human adult (weighing approximately 70 kilograms), from about 5 mg to about 3000 mg, more preferably from about 5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg, of Formula (I) compound are administered per day for systemic administration. It is understood that these dosage ranges are by way of example only, and that daily administration can be adjusted depending on the factors listed above.

A preferred method of administration for treatment of rheumatoid arthritis is oral or parenterally via intra-articular injection. As is known and practiced in the art, all formulations for parenteral administration must be sterile. For mammals, especially humans, (assuming an approximate body weight of 70 kilograms) individual doses of from about 10 mg to about 1000 mg are preferred.

A preferred method of systemic administration is oral. Individual doses of from about 10 mg to about 1000 mg, preferably from about 10-mg to about 300 mg are preferred.

Topical administration can be used to deliver the Formula (I) compound systemically, or to treat a subject locally. The amounts of Formula (I) compound to be topically administered depends upon such factors as skin sensitivity, type and location of the tissue to be treated, the composition and carrier (if any) to be administered, the particular Formula (I) compound to be administered, as well as the particular disorder to be treated and the extent to which systemic (as distinguwashed from local) effects are desired.

The inhibitors of the invention can be targeted to specific locations where the metalloprotease is accumulated by using targeting ligands. For example, to focus the inhibitors to metalloprotease contained in a tumor, the inhibitor is conjugated to an antibody or fragment thereof which is immunoreactive with a tumor marker as is generally understood in the preparation of immunotoxins in general. The targeting ligand can also be a ligand suitable for a receptor which is present on the tumor. Any targeting ligand which specifically reacts with a marker for the intended target tissue can be used. Methods for coupling the invention compound to the targeting ligand are well known and are similar to those described below for coupling to carrier. The conjugates are formulated and administered as described above.

For localized conditions, topical administration is preferred. For example, to treat ulcerated cornea, direct application to the affected eye may employ a formulation as eyedrops or aerosol. For corneal treatment, the compounds of the invention can also be formulated as gels, drops or ointments, or can be incorporated into collagen or a hydrophilic polymer shield. The materials can also be inserted as a contact lens or reservoir or as a subconjunctival formulation. For treatment of skin inflammation, the compound is applied locally and topically, in a gel, paste, salve or ointment. The mode of treatment thus reflects the nature of the condition and suitable formulations for any selected route are available in the art.

In all of the foregoing, of course, the compounds of the invention can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.

Some of the compounds of the invention also inhibit bacterial metalloproteases. Some bacterial metalloproteases may be less dependent on the stereochemistry of the inhibitor, whereas substantial differences are found between diastereomers in their ability to inactivate the mammalian proteases. Thus, this pattern of activity can be used to distinguish between the mammalian and bacterial enzymes.

Preparation and Use of Antibodies:

The invention compounds can also be utilized in immunization protocols to obtain antisera immunospecific for the invention compounds. As the invention compounds are relatively small, they are advantageously coupled to antigenically neutral carriers such as the conventionally used keyhole limpet hemocyanin (KLH) or serum albumin carriers. For those invention compounds having a carboxyl functionality, coupling to carrier can be done by methods generally known in the art. For example, the carboxyl residue can be reduced to an aldehyde and coupled to carrier through reaction with sidechain amino groups in protein-based carriers, optionally followed by reduction of imino linkage formed. The carboxyl residue can also be reacted with sidechain amino groups using condensing agents such as dicyclohexyl carbodiimide or other carbodiimide dehydrating agents.

Linker compounds can also be used to effect the coupling; both homobifunctional and heterobifunctional linkers are available from Pierce Chemical Company, Rockford, Ill. The resulting immunogenic complex can then be injected into suitable mammalian subjects such as mice, rabbits, and the like. Suitable protocols involve repeated injection of the immunogen in the presence of adjuvants according to a schedule which boosts production of antibodies in the serum. The titers of the immune serum can readily be measured using immunoassay procedures, now standard in the art, employing the invention compounds as antigens.

The antisera obtained can be used directly or monoclonal antibodies may be obtained by harvesting the peripheral blood lymphocytes or the spleen of the immunized animal and immortalizing the antibody-producing cells, followed by identifying the suitable antibody producers using standard immunoassay techniques.

The polyclonal or monoclonal preparations are then useful in monitoring therapy or prophylaxis regimens involving the compounds of the invention. Suitable samples such as those derived from blood, serum, urine, or saliva can be tested for the presence of the administered inhibitor at various times during the treatment protocol using standard immunoassay techniques which employ the antibody preparations of the invention.

The invention compounds can also be coupled to labels such as scintigraphic labels, e.g., technetium 99 or I-131, using standard coupling methods. The labeled compounds are administered to subjects to determine the locations of excess amounts of one or more metalloproteases in vivo. The ability of the inhibitors to selectively bind metalloprotease is thus taken advantage of to map the distribution of these enzymes in situ. The techniques can also be employed in histological procedures and the labeled invention compounds can be used in competitive immunoassays.

The following non-limiting examples illustrate the compounds, compositions, and uses of the present invention.

EXAMPLES

Compounds are analyzed using¹H and ¹³C NMR, Elemental analysis, mass spectra and/or IR spectra, as appropriate.

Typically tetrahydrofuran (THF) is distilled from sodium and benzophenone, diisopropylamine is distilled from calcium hydride and all other solvents are purchased as the appropiate grade. Chromatography is performed on silica gel (70-230 mesh; Aldrich) or (230-400 mesh; Merk) as appropriate. Thin layer chromatography analysis (TLC) is performed on glass mounted silicia gel plates (200-300 mesh; Baker) and visualized with UV or 5% phosphomolybdic acid in EtOH.

Examples 1-25

The following chart shows the structure of compounds made according to the description in Examples 1-19 described below:

Example * (configuration) Y Z  1 d a-OH H  2 d b-OH H  3 l a-OH H  4 l b-OH H  5 d b-OMe H  6 d b-(2-benzathiazole) H  7 d a-(2-benzathiazole) H  8 d b-2(3N-methyl-imidazole) H  9 d a-2(3N-methyl-imidazole) H 10 d b-OPh H 11 d b-O(C₆H₄)OCH₂Ph H 12 d b-O(2-(C₆H₄)NHPh) H 13 d b-O(3-Pyridyl) H 14 d b-SPh H 15 d b-S(4-C₆H₄OMe) H 16 d b-S(3-C₆H₄OMe) H 17 d a-OCH₂OCH₂CH₃ H 18 d a-OCH₂OCH₂Ph H 19 d a-OCH₂OCH₂CH₃OCH₃ H 20 d b-SH H 21 racemic H phenyl 22 d a-OH, b-Et H 23 d a-OH, b-Ph H 24 d b-O(4-C₆H₄-Octyl) H 25 d a-OH gem-(CH₃)₂ Ph-phenyl Me = methyl C₆H₄-phenyl diradical

Example 1

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-4R-hydroxy-pyrrolidine:     cis-Hydroxy-D-proline (50 g, 0.38 mole) is dissolved in     water:dioxane (1:1, 300 mL) with triethylamine (135 mL, 0.96 mole).     4-Methoxyphenylsulfonyl chloride (87 g, 0.42 mole) is added along     with 2,6-dimethylaminopyridine (4.6 g, 0.038 mole) and the mixture     is stirred 14 hr. at room temperature. The mixture is then     concentrated and diluted with EtOAc. Layers are separated and the     organic layer is washed 2× with 1N HCl, 1× with brine, dried over     MgSO₄, filtered and evaparated to give 83 g of solid material which     is dissolved in MeOH (500 mL). Thionyl chloride (50 mL) is added     dropwise and the resulting mixture stirred for 14 hr. The mixture is     then evaparated to dryness and triturated with CHCl₃ to give a white     solid which is sufficiently pure to carry forward without     purification. CI⁺ MS: m/z (rel intensity) 316 (M⁺+H, 100), 256(30),     146(45). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-hydroxypyrrolidine:     The starting methylester 1a (361 mg, 1.15 mmole) is taken in 1 mL of     methanol, treated with NH₂OK (1.45 mL, 0.86 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning the material is     concentrated and partitioned between EtOAc and 1N HCl. The organic     layer is washed with brine, dried over MgSO₄, filtered and     evaparated to give crude material which is recrystallized from     hex:EtOAc at −4° C. to give the desired white solid and recovered     oil. ESI MS: m/z (rel intensity) 317 (M+H⁺, 100), 334 (M+NH₄ ⁺, 20),     339 (M+Na⁺, 35).

Example 2

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-benzoyloxypyrrolidine:     The alcohol 1a (780 mg, 2.48 mmole) is dissolved in 5 mL of     methylene chloride. Benzoic acid (604 mg, 4.95 mmole) and triphenyl     phosphine (779 mg, 2.98 mmole) are then added, followed by diethyl     azodicarboxylate (429 mL, 2.73 mmole). After 3 hrs, the reaction     mixture is filtered and silica gel is added to the filtrate to     adsorb the solutes and the mixture is concentrated to dryness. The     resulting solid mixture is poured onto the top of a flash silica     column which is eluted with hex:EtOAc (1:1 to 0:1) to give the     desired product as a white solid. CI⁺ MS: m/z (rel intensity) 420.0     (M⁺+H, 100), 250.1 (95), 126.0 (45). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-hydroxypyrrolidine:     The methyl-benzyl diester 2a (175 g, 0.418 mmole) is taken in 2.5 mL     of methanol, treated with NH₂OK (0.48 mL, 0.86 M in methanol,     solution prepared as described in Fieser and Fieser, Vol 1, p 478)     and stirred overnight. The following morning, dry silica (1 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with EtOAc:MeOH HCO₂H (90:9:1) to give a white     solid which is then recrystallized from hexane:EtOAc (1:5) to give     white crystals. ESI MS: m/z (rel intensity) 317.1 (M⁺+H, 100), 339.1     (M⁺+Na, 20).

Example 3

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2S)-carbomethoxy-(4R)-hydroxypyrrolidine:     To a solution of trans-4-hydroxy-L-proline methyl ester (2.0 g, 11.0     mmol) in 10 mL DMF is added 2 mL N-methylmorpholine and     4-methoxybenzenesulfonyl chloride and is stirred for 1 hr. The     solution is then partitioned between EtOAc and water, washed with 1     N HCl, NaHCO₃, NaCl, and dried over MgSO₄. The crude product is then     chromatographed over silica with EtOAc to give the title compound.     CI⁺ MS: m/z (rel intensity) 316 (100, M⁺+H). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2S)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine:     The starting ester 3a (500 mg, 1.6 mmol) is added to NH₂OK (1.9 mL,     1 eq in MeOH, prepared according to Fieser and Fieser, Vol 1, p 478)     and stirred for 15 hr. The solvent is evaporated and the residue is     dissolved in 1N HCl and extracted with EtOAc. The organic layer is     dried over MgSO₄, evaporated and the residue is recrystallized from     EtOAc:Hexanes to give the title compound. ESI MS: m/z (rel     intensity) 317 (100, M⁺+H), 256 (70).

Example 4

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2S)-carbomethoxy-(4S)-hydroxy-pyrrolidine:     To a solution of cis-4-hydroxy-L-proline methyl ester (2.0 g, 11.0     mmol) in 10 mL DMF is added 2 mL N-methylmorpholine and     4-methoxybenzenesulfonyl chloride and is stirred for 1 hr. The     solution is then partitioned between EtOAc and water, washed with 1     N HCl, NaHCO₃, NaCl, and dried over MgSO₄. The crude product is then     chromatographed over silica with EtOAc to give the tide compound.     CI⁺ MS: m/z (rel intensity) 316 (100, M⁺+H). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2S)-N-hydroxycarboxamido-(4S)-hydroxy-pyrrolidine:     The starting ester 4a (500 mg, 1.6 mmol) is added to NH₂OK (1.9 mL,     1 eq in MeOH, prepared according to Fieser and Fieser, Vol 1, p 478)     and stirred for 15 hr. The solvent is evaporated and the residue is     dissolved in 1N HCl and extracted with EtOAc. The organic layer is     dried over MgSO₄, evaporated and the residue is recrystallized from     EtOAc:Hexanes to give the title compound. ESI MS: m/z (rel     intensity) 317 (100, M⁺+H), 256 (70).

Example 5

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carboxy-(4S)-hydroxy-pyrrolidine:     The diester 2a (10 g, 24 mmole) is dissolved in water:dioxane (1:10,     50 mL) and stirred overnight in the presence of lithium hydroxide     monohydrate (5 g, 120 mmole). The mixture is acidified with 1N HCl     and extracted with EtOAc, washed with brine, dried over MgSO₄,     filtered and evaparated to give solid material which is     recrystallized from EtoAc:hexanes to give the title compound as a     white solid. ESI MS: m/z (rel intensity) 302 (M⁺+H, 100), 318     (M⁺+NH₃, 30). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-methoxy-pyrrolidine:     The carboxylic acid 5a (4.0 g, 13.2 mmol) is stirred in THF at room     temperature and then sodium hydride (1.58 g, 39.6 mmol, 3 equiv, 60%     in oil) is slowly added. After hydrogen gas evolution had ceased,     methyl iodide (5.52 g, 39.6 mmol, 3 equiv) is added to the reaction     mixture. The resulting solution is stirred at room temperature for 1     hour. The reaction mixture is quenched by the addition of water and     then extracted with EtOAc. The organic extracts are concentrated to     an oil and then methanol and 3 drops of conc. HCl are added. The     solution is then heated to reflux for 24 hours. The solvent is     removed and the product is purified by silica gel chromatography     (1/1 hexane/EtOAc followed by 100% EtOAc) to afford the desired     methyl ester as a white crystalline solid. CI⁺ MS: m/z (rel     intensity) 330 (M⁺, 100). -   c.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-methoxypyrrolidine:     The ester 5b (0.50 g, 1.52 mmol) is taken in 2 mL of methanol,     treated with NH₂OK (2.5 mL, 0.86 M in methanol, solution prepared as     described in Fieser and Fieser, Vol 1, p 478) and stirred overnight.     The solution is poured into water and acidified to pH˜2. The     resulting solution is extracted with CH₂Cl₂, dried (Na₂SO₄) and     concentrated to a white solid. Purification of the resulting solid     is accomplished by recrystallization from EtOAc:hexane (3:1) to     afford the desired product as a white crystalline solid. ESI MS: m/z     (rel intensity) 331.0 (M+H⁺, 100), 348.0 (M+NH₄ ⁺, 85), 353.0     (M+Na⁺, 45).

Example 6

-   a.     (1N)-4-Methoxyphenylsulfonamido-(2R)-carbomethoxy-(4R)-trifluoromethanesulfonyl-pyrrolidine:     The starting alcohol 1a (221 mg, 0.702 mmole) is taken in dry CH₂Cl₂     under argon and cooled to 0° C. 2,6-Lutidine (326 mL, 2.81 mmole) is     added via syringe followed by slow syringe addition of     trifluoromethanesulfonyl anhydride (153 mL, 0.912 mmole) and the     resulting yellow mixture is 1 hr at 0° C. and then partitioned     between water and EtOAc. The organic layer is dried over MgSO₄,     filtered and evaparated. The crude residue is chromatogaphed over     flash silica with hexane:EtOAc (4:1 to 1:1) to give the desired     off-white solid. CI⁺ MS: m/z (rel intensity) 411 (M+NH₄ ⁺, 25) 394     (M⁺+H, 21), 224 (82), 155 (23), 128 (100). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(2-mercapto-benzothiazolyl)-pyrrolidine:     The triflate 6a (145 mg, 0.353 mmole) is dissolved in methylene     chloride (1 mL) under argon and 2,6-lutidine (61 mL, 0.529 mmole) is     added via syringe followed by 2-mercapto-benzothiazole (65 mg, 0.388     mmole). After 1 hr., silica gel (1.5 mL) is added to the mixture     which is then evaparated to dryness. The resulting solid mixture is     then added to the top of a flash silica column which is then eluted     with hexane:EtOAc (1:1 to 1:5) to give the pure title compound as a     clear oil. CI⁺ MS: m/z (rel intensity) 465 (M⁺+H, 10), 300 (38), 240     (13), 168 (21), 150 (33), 136 (100). -   c.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(2-mercapto-benzothiazolyl)-pyrrolidine:     A 1.76M solution of potassium hydroxyl amine in methanol is     prepared. The 1.76M solution (0.4 mL, 0.711 mmoles) is added     directly to the methyl ester 6b (0.165 g, 0.356 mmoles) and the     reaction mixture stirred overnight. The solution is acidified with     1N HCl, then extracted 3 times with ethyl acetate, dried with     magnesium sulfate, filtered and evaporated. Chromatography is     performed on silica gel using ethyl acetate:hexane:formic acid     (1:1:0.1) to give the title compound. ESI MS: m/z (rel intensity)     466.0 (M⁺+H, 100), 408.2 (M⁺+Na, 20).

Example 7

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-hydroxy-pyrrolidine:     The acid 5a (4 g, 9.55 mmole) is dissolved in methanol (50 mL),     treated with thionyl chloride (3 mL) and stirred overnight. The     mixture is then evaparated to dryness and recrystallized from     EtOAc:hexanes to give the title compound as a white solid. CI⁺ MS:     m/z (rel intensity) 316 (M⁺+H, 100), 256 (60), 158 (25), 146 (30). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-(2-mercaptobenzothiazolyl)-pyrrolidine:     The starting alcohol 7a (323 mg, 1.03 mmole) is taken in 4 mL of     CH₂Cl₂ and to this mixture is added triphenylphosphene (351 mg, 1.35     mmole), 2-mercaptobenzothiazole (189 mg, 1.13 mg), and     diethyl-diazadicarboxylate (195 mM, 1.24 mmole) and the mixture is     stirred for 0.5 hr. at which time 5 mL of silica gel is added to the     mixture which is then concentrated to dryness. The dry residue is     poured onto the top of a flash silica column and eluted with     hexane:EtOAc (4:1 to 1:4) to give a clear oil. CI⁺ MS:m/z (rel     intensity) 465 (M⁺+H, 5), 300 (20), 150 (25), 136 (100), 128 (25). -   c.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-(2-mercaptobenzothiazolyl)-pyrrolidine:     The methyl ester 7b (372 g, 0.802 mmole) is taken in 1.5 mL of     methanol, treated with NH₂OK (1.4 mL, 0.86 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (1.5 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with hexane EtOAc (1:2) to remove impurities and     then EtOAC:MeOH (9:1). The resulting product is recrystallized from     chloroform to give white crystals. ESI MS: m/z (rel intensity) 466.1     (M⁺+H, 100), 488.0 (M⁺+Na, 12).

Example 8

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-[(1N)-methyl-2-mercaptoimidazyl]-pyrrolidine:     The alcohol 1a (700 mg, 2.22 mmole) is dissolved in 12 mL of     methylene chloride. 2-Mercapto-1-methylimidazole (304 mg, 2.66     mmole) and triphenyl phosphine (873 mg, 3.33 mmole) are then added,     followed by diethyl azodicarboxylate (420 mL, 2.66 mmole). After 3     hrs, the reaction mixture is filtered and silica gel is added to the     filtrate to adsorb the solutes and the mixture is concentrated to     dryness. The resulting solid mixture is poured onto the top of a     flash silica column which is eluted with hex:EtOAc (1:1 to 0:1) to     give the desired product as a white solid. CI⁺ MS: m/z (rel     intensity) 412 (M⁺+H, 100), 242 (5), 115 (28). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-[(1N)-methyl-2-mercaptoimidazyl]-pyrrolidine:     The ester 8a (500 mg, 1.22 mmole) is taken in 1 mL of methanol,     treated with NH₂OK (2.11 mL, 0.86 M in methanol, solution prepared     as described in Fieser and Fieser, Vol 1, p 478) and stirred     overnight. The following morning, dry silica (2 mL) is added to the     mixture and the solvent removed under vaccuum. The dry silica is     poured on the top of a flash silica gel column which is subsequently     eluted with hexane:EtOAc (1:1 to 0:1) followed by EtOAc:MeOH:NH₄OH     (9:1:0.1) to give a white solid. ESI MS: m/z (rel intensity) 413     (M⁺+H, 100), 435 (M⁺+Na, 20).

Example 9

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-[(1N)-methyl-2-mercaptoimidazyl]-pyrrolidine:     The alcohol 7a (700 mg, 2.22 mmole) is dissolved in 12 mL of     methylene chloride. 2-Mercapto-1-methylimidazole (304 mg, 2.66     mmole) and triphenyl phosphine (873 mg, 3.33 mmole) are then added,     followed by diethyl azodicarboxylate (420 mL, 2.66 mmole). After 3     hrs, the reaction mixture is filtered and silica gel is added to the     filtrate to adsorb the solutes and the mixture is concentrated to     dryness. The resulting solid mixture is poured onto the top of a     flash silica column which is eluted with hex:EtOAc (1:1 to 0:1) to     give the desired product as a white solid. CI⁺ MS: m/z (rel     intensity) 412 (M⁺+H, 100), 242 (5), 115 (28). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-[(1N)-methyl-2-mercaptoimidazyl]-pyrrolidine:     The ester 9a (500 mg, 1.22 mmole) is taken in 5 mL of methanol,     treated with NH₂OK (2.11 mL, 0.86 M in methanol, solution prepared     as described in Fieser and Fieser, Vol 1, p 478) and stirred     overnight. The following morning, dry silica (2 mL) is added to the     mixture and the solvent removed under vaccuum. The dry silica is     poured on the top of a flash silica gel column which is subsequently     eluted with hexane:EtOAc (1:1 to 0:1) to give a white solid. ESI MS:     m/z (rel intensity) 413.0 (M⁺+H, 100), 435.0 (M⁺+Na, 20).

Example 10

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-phenoxy-pyrrolidine:     The alcohol 1a (1.3 g, 4.12 mmole) is dissolved in 3 mL of methylene     chloride. Phenol (0.8 g, 8.24 mmole) and triphenyl phosphine (2.16     g, 8.24 mmole) are then added, followed by diethyl azodicarboxylate     (1.2 mL, 7.84 mmole). After 3 hrs, the reaction mixture is filtered     and concentrated to an oil, which is purified on silica gel using     ethyl acetate:hexane:methylene chloride (1:3:1) to give the desired     product as an oil. CI⁺ MS: m/z (rel intensity) 409 (100, M⁺+NH₃),     392 (72, M⁺+H). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-phenoxypyrrolidine:     The methyl ester 10a (0.6 g, 1.53 mmole) is taken in 3 mL of     methanol, treated with NH₂OK (5 mL, 1.7 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (1.5 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with formic acid:EtOAc (0:1 to 3:97) to give     0.36 g of white foamy solid, which is recrystallized from     hexane:EtOAc to give the desired product. ESI MS: m/z (rel     intensity) 415 (38, M⁺+Na), 410 (10, M⁺+NH₄), 393 (100, M⁺+H).

Example 11

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-[(4-benzyloxy)-phenoxy]-pyrrolidine:     Triphenylphosphine (2.5 g, 9.51 mmole) is dissolved in 20 mL of THF.     Diethyl azodicarboxylate (1.9 mL, 9.51 mmole) is added dropwise at     0° C. After 30 min with stirring, a solution of 4-(benzyloxy)phenol     (2.38 g, 11.9 mmole) and the alcohol 1a (1.5 g, 4.76 mmole) in 15 mL     of TVF is added dropwise. The reaction is stirred at 0° C. for 30     min., room temperature overnight and concentrated to an oil. The     crude product is purified by flash chromatography (hexane/EtOAc, 4:1     to 1:1) on silica gel to give the desired product. CI⁺ MS: m/z (rel     intensity) 498 (100, M⁺+H), 328 (24). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(4-benzyloxy)-phenoxypyrrolidine:     The methyl ester 11a (0.7 g, 1.4 mmole) is taken in 1 mL of     methanol, treated with NH₂OK (8 ml, 1.7 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred for 3 hr. Silica (1.5 mL) is added to the mixture and the     solvent is removed under vaccuum. The dry silica is poured on the     top of a flash silica gel column which is subsequently eluted with     hexane:EtOAc (1:1) to EtOAc:CH₃OH (1:0 to 1:1) to give the desired     product as a white foamy solid. ESI MS: m/z (rel intensity) 521 (30,     M⁺+Na), 516 (14, M⁺+NH₄), 499(100, M⁺+H).

Example 12

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(3-N-phenyl-amino)-phenoxylpyrrolidine:     Triphenylphosphine (2.5 g, 9.52 mmole) is dissolved in 20 mL of THF.     Diethyl azodicarboxylate (1.95 mL, 9.52 mmole) is added dropwise at     0° C. After 30 min with stirring, a solution of     3-hydroxydiphenylamine (2.2 g, 11.9 mmole) and the alcohol 1a (1.5     g, 4.76 mmole) in 15 mL of THF is added dropwise. The reaction is     stirred at 0° C. for 30 min., room temperature for 2 hr and     concentrated to an oil. The crude product is purified by flash     chromatography (hexane/EtOAc, 7:3 to 1:1) on silica gel to give the     desired product. ESI MS: m/z (rel intensity) 505 (8, M⁺+Na), 483     (100, M⁺+H). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(3-N-phenylamino)-phenoxylpyrrolidine:     The methyl ester 12a (0.68 g, 1.38 mmole) is taken in 2 mL of     methanol, treated with NH₂OK (6 ml, 1.7 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (1.5 mL) is     added to the mixture and the solvent is removed under vaccuum. The     dry silica is poured on the top of a flash silica gel column which     is subsequently eluted with EtOAc:CH₃OH (1:0 to 9:1) to give the     desired product as a white foamy solid. ESI MS: m/z (rel intensity)     506 (36, M⁺+Na), 484 (100, M⁺+H).

Example 13

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(3-pyridinoxy)-pyrrolidine:     Triphenylphosphine (2.42 g, 9.2 mmole) is dissolved in 20, mL of     THF. Diethyl azodicarboxylate (1.81 mL, 9.2 mmole) is added dropwise     at 0° C. After 30 min with stirring, a solution of 3-hydroxypyridine     (1.32 g, 13.83 mmole) and the alcohol 1a (1.5 g, 4.61 mmole) in 15     mL of THF is added dropwise. The reaction is stirred at 0° C. for 30     min., room temperature for 2 hr and concentrated to an oil. The     crude product is purified by flash chromatography (hexane/EtOAc: 1/1     to EtOAc) on silica gel to give the desired product. CI⁺ MS: m/z     (rel intensity) 393 (100, M⁺+H), 279 (88), 223 (70). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-phenoxypyrrolidine:     The methyl ester 13a (0.18 g, 0.46 mmole) is taken in 1 mL of     methanol, treated with NH₂OK (0.5 ml, 1.7 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (1.5 mL) is     added to the mixture and the solvent is removed under vaccuum. The     dry silica is poured on the top of a flash silica gel column which     is subsequently eluted with EtOAc:CH₃OH (1:0 to 1:1) to give a white     foamy solid which is crystallized from methylene chloride to give     the desired product as a white solid. ESI MS: m/z (rel intensity)     432 (10, M⁺+K), 416 (8, M⁺+Na), 394 (100, M⁺+H).

Example 14

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-mercaptophenylpyrrolidine:     The alcohol 1a (200 mg, 0.634 mmole) is dissolved in 2 mL of     methylene chloride. Thiophenol (78 mL, 0.671 mmole) and triphenyl     phosphine (250 mg, 0.951 mmole) are then, added, followed by diethyl     azodicarboxylate (120 mL, 0.761 mmole). After 3 hrs, the reaction     mixture is filtered and silica gel is added to the filtrate to     adsorb the solutes and the mixture is concentrated to dryness. The     resulting solid mixture is poured onto the top of a flash silica     column which is eluted with hex:EtOAc (1:1 to 0:1) to give the     desired white solid. CI⁺ MS: m/z (rel intensity) 408 (M⁺+H, 15), 238     (100), 128 (99), 109 (93). -   b.     (1N)-4-Methoxyphenylsulfonamido-(2R)-N-hydroxycarboxamido-(4S)-mercaptophenylpyrrolidine:     The starting methylester 14a (169 mg, 0.415 mmole) is taken in 1 mL     of methanol, treated with NH₂OK (0.725 mL, 0.86 M in methanol,     solution prepared as described in Fieser and Fieser, Vol 1, p 478)     and stirred overnight. The following morning, dry silica (1.5 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (1:1 to 0:1) and then with     EtOAc:MeOH:NH₄OH (9:1:0.1) to give a white solid. ESI MS: m/z (rel     intensity) 409.2 (M⁺+H, 100), 426.2 (M⁺+NH₄, 12), 431.1 (M⁺+Na, 25).

Example 15

-   a.     (1N)-4-Methoxyphenylsulfonamido-(2R)-carbomethoxy-(4R)-methane-sulfonyl-pyrrolidine:     The starting alcohol 1a (17.9 g, 57 mmole) is taken in dry CH₂Cl₂     (100 mL) in the presence of Et₃N (25 mL) at room temperature.     Methanesulfonyl chloride (4.87 mL, 63 mmole) is added dropwise and     the resulting mixture is stirred overnight and the following morning     the mixture is partioned between water and EtOAc. The organic layer     is washed with brine, dried over MgSO₄, filtered and evaparated. The     resulting solid is recrystallized from EtOAc:hexanes to give the     title compound as white prisms. CI⁺ MS: m/z (rel intensity) 411     (M+NH₄ ⁺, 25) 394 (M⁺+H, 21), 224 (82), 155 (23), 128 (100). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(4-methoxy-mercaptophenyl)-pyrrolidine:     The starting mesylate 15a (267 mg, 0.68 mmole) and     4-methoxythiophenol (88 mL, 0.713 mmole) are taken in THF (4 mL) at     room temperature under argon and ^(t)butoxide (78 mg, 0.713 mmole)     is added. The mixture is stirred for 1 hr and then partitioned     between EtOAc and 1N HCl. The organic layer is washed with brine,     dried over MgSO₄, filtered and evaparated to give 354 mg of residue     which is then chromatographed over flash silica with hexane:EtOAc     (8:1 to 2:1) to give the title compound as a clear oil. CI⁺ MS: m/z     (rel intensity) 438 (M⁺+H, 50), 268 (100), 208 (21), 155 (81), 128     (79), 109 (45). -   c.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(4-methoxy-phenylthioloxy)-pyrrolidine:     The starting methylester 15b (129 mg, 0.295 mmole) is taken in 1 mL     of methanol, treated with NH₂OK (0.85 mL, 0.86 M in methanol,     solution prepared as described in Fieser and Fieser, Vol 1, p 478)     and stirred overnight. The following morning, dry silica (1.5 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (1:2 to 0:1) to give a clear     glass which is puffed into a foamy solid by slight heating under     vacuum. ESI MS: m/z (rel intensity) 439 (M⁺+H, 100), 456 (M⁺+NH₃,     30).

Example 16

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(3-methoxy-mercaptophenyl)-pyrrolidine:     The starting mesylate 15a (267 mg, 0.68 mmole) and     3-methoxythiophenol (88 mL, 0.713 mmole) are taken in THF (4 mL) at     room temperature under argon and ^(t)butoxide (78 mg, 0.713 mmole)     is added. The mixture is stirred for 1 hr and then partitioned     between EtOAc and 1N HCl. The organic layer is washed with brine,     dried over MgSO₄, filtered and evaparated to give a residue which is     then chromatographed over flash silica with hexane:EtOAc (8:1 to     2:1) to give the title compound as a clear oil. CI⁺ MS: m/z (rel     intensity) 438.0 (M+H⁺, 17), 268.0 (100), 155 (65). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(3-methoxy-mercaptophenyl)-pyrrolidine:     The starting methylester 16a (1.58 mg, 0.361 mmole) is taken in 5 mL     of methanol, treated with NH₂OK (0.624 mL, 0.86 M in methanol,     solution prepared as described in Fieser and Fieser, Vol 1, p 478)     and stirred overnight. The following morning, dry silica (2 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (1:1 to 0:1) then with     EtOAc:MeOH:NH₄OH (9:1:0.1) to give a white solid. ESI MS: m/z (rel     intensity) 439 (M⁺+H, 10), 456.0 (M⁺+NH₄ ⁺, 40), 461.0 (M⁺+Na⁺, 27).

Example 17

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-ethyloxymethoxy-pyrrolidine:     Chloroethylmethylether (0.884 mL, 9.54 mmole) was added dropwise to     a stirred solution of the methylester 1a (1.00 g, 3.18 mmole) in     CH₂Cl₂ (12 mL) and DIPEA (0.830 mL) and stirred for 16 hrs.     Additional CH₂Cl₂ was added and the mixture was washed with     saturated NaHSO₄, dried over sodium sulfate and the solvent removed     under vacuum. The dried material was purified over a silica column     eluting first with hexane:EtOAc (8:2), followed with hexane:EtOAc     (1:1) then with EtOAc to give a colorless oil. ESI MS: m/z (rel     intensity) 374.02 (M⁺+H, 100), 391.03 (M⁺+NH₃, 70). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-ethyloxymethoxy-pyrrolidine:     The starting methyl ester 17a (1.13 g, 3.03 mmole) is taken in 4 mL     of methanol:tetrahydrofuran (1:1), and treated with NH₂OK (4 mL,     1.25M in methanol) and stirred overnight. The following morning, dry     silica (2.5 mL) is added to the mixture and the solvent removed     under vacuum. The dry silica is poured on top of a flash silica     column which is subsequently eluted with ethyl acetate followed with     ethyl acetate:methanol (8:2) to give a clear glass which is puffed     to a foamy solid by slight heating under vacuum. The product was     recrystallized from cold EtOAc:hexane to give white powder. ESI MS:     m/z (rel intensity) 374.02 (M⁺+H, 100), 391.03 (M⁺+NH₃, 70).

Example 18

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-benxyloxy-methoxy-pyrrolidine:     Benzylchloromethylether (2.25 g, 9.54 mmole) is added dropwise to a     stirred solution of the methylester 1a (1.00 g, 3.18 mmole) in     CH₂Cl₂ (12 mL) and DIPEA (0.830 mL, 4.77 mmole) and stirred for four     days. Additional CH₂Cl₂ is added and the mixture washed with     saturated NaH₂SO₄, dried over sodium sulfate and the solvent removed     under vacuum. The dried material is purified over a silica column     eluting first with hexane, then with hexane:EtOAc (7:3) to give a     colorless oil. ESI MS: m/z (rel intensity) 436.07 (M⁺+H, 100),     453.09 (M⁺+NH₃, 70) -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-benxyl-oxymethoxy-pyrrolidine:     The starting methyl ester 18a (1.00 g, 2.29 mmole) is taken in 2 ml     of methanol/tetrahydrofuran (1:1), and treated with NH₂OK (2 ml,     1.25M in methanol) and stirred overnight. The following morning, dry     silica (1.5 ml) is added to the mixture and the solvent removed     under vacuum. The dry silica is poured on top of a flash silica     column which is subsequently eluted with hexane:ethyl acetate (7:3)     followed with ethyl acetate to give a clear glass which is dried to     a foamy solid by slight heating under vacuum. The product was     recrystallized from cold methanol to give white powder. ESI MS: m/z     (rel intensity) 436.98 (M⁺+H, 100), 453.97 (M⁺+NH₃, 30).

Example 19

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-(2-methoxyethyl-oxy)-methoxypyrrolidine:     MEM chloride (1.09 mL, 9.54 mmole) is added dropwise to a stirred     solution of the alcohol 1a (1.00 g, 3.18 mmole) in CH₂Cl₂ (12 mL)     and DIPEA (0.830 mL) and stirred for 16 hrs. Additional CH₂Cl₂ is     added and the mixture is washed with saturated NaH₂SO₄, dried over     sodium sulfate and the solvent removed under vacuum. The dried     material was purified over a silica column eluting first with     hexane:EtOAc (1:1) to give a colorless oil. ESI MS: m/z (rel     intensity) 403.99 (M⁺+H, 70), 421.01 (M⁺+NH₃, 100). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-(2-methoxyethyl-oxy)-methoxypyrrolidine:     The starting methyl ester 19 (450 mg, 1.12 mmole) is taken in 2 mL     of methanol:tetrahydrofuran (1:1), and treated with NH₂OK (2 mL,     1.25M in methanol) and stirred overnight. The following morning, dry     silica (1.5 mL) is added to the mixture and the solvent removed     under vacuum. The dry silica is poured on top of a flash silica     column which is subsequently eluted with EtOAC followed with ethyl     acetate:methanol (8:2) to give a clear glass which is puffed to a     foamy solid by slight heating under vacuum. The product was     recrystallized from cold EtOAc:hexane to give white powder. ESI MS:     m/z (rel intensity) 405.05 (M⁺+H, 100), 422.01 (M⁺+NH₃, 20).

Example 20

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-thioacetoxyl-pyrrolidine:     Triphenylphosphine (0.9 g, 3.42 mmole) is dissolved in 12 mL of THF.     Diethyl azodicarboxylate (0.54 mL, 3.42 mmole) is added dropwise at     0° C. After 30 min with stirring, a solution of thioacetic acid (0.4     mL, 5.13 mmole) and the alcohol 1a (0.54 g, 1.71 mmole) in 10 mL of     THF is added dropwise. The reaction is stirred at 0° C. for 30 min.,     room temperature for 2 hr and concentrated to an oil. The crude     material is purified by flash chromatography (CH₂Cl₂:hexane (1:1) to     CH₂Cl₂:EtOAc; (50:1) to CH₂Cl₂:EtOAc; 25:1) on silica gel to give     the desired product. ESI MS: m/z (rel intensity) 391 (100, M⁺+NH₃),     374 (65, M⁺+H). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-hydroxycarboxamido-(4S)-thio-pyrrolidine:     The thioester 20a (0.4 g, 1.07 mmole) is dissolved in 2 mL of     methanol and degassed by argon. A solution of NH₂OK (6.1 mL, 1.7 M     in methanol, solution prepared as described in Fieser and Fieser,     Vol 1, p 478) is also degassed and added to the thioester solution.     After 2 hr with stirring, the reaction is acidified with 1N HCl,     concentrated to remove solvent, then distributed between HCl and     ethyl acetate. The ethyl acetate layer is washed with brine, dried     over MgSO₄ and concentrated to an oil. The crude product is purified     by flash chromatography (1% formic acid in EtOAc) on silica gel to     give the desired product. ESI MS: m/z (rel intensity) 333 (90,     M⁺+H).

Example 21

-   a.     (±)-(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(3S)-phenyl-pyrrolidine:     (±)-trans-3-phenylproline (403 mg, 1.73 mmole, prepared as described     in J. Med. Chem. 1994, 37, 4371.) is dissolved in water:dioxane     (1:1, 5 mL) with triethylamine (0.6 mL, 4.33 mmole).     4-Methoxyphenylsulfonyl chloride (393 mg, 1.9 mmole) is added along     with 2,6-dimethylaminopyridine (catalytic) and the mixture is     stirred 14 hr. at room temperature. The mixture is then concentrated     and diluted with EtOAc. Layers are separated and the organic layer     is washed 2× with 1N HCl, 1× with brine, dried over MgSO₄, filtered     and evaparated to give 623 mg of solid material which is dissolved     in MeOH (15 mL). Thionyl chloride (1.5 mL) is added dropwise and the     resulting mixture stirred for 14 hr. Silica gel (4 mL) is added and     the mixture concentrated. The resulting powder is poured onto a     flash silica column and eluted with hexane:EtOAc (1:1 to 0:1) to     give the title compound. ESI MS: m/z (rel intensity) 376.1 (M⁺+H,     100), 316.1 (22). -   b.     (±)-(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(3S)-phenylpyrrolidine:     The methylester 21a (0.262 g, 0.699 mmole) is taken in 1 mL of     methanol, treated with NH₂OK (1.2 mL, 0.86 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (2 mL) is added     to the mixture and the solvent removed under vaccuum. The dry silica     is poured on the top of a flash silica gel column which is     subsequently eluted with hexane EtOAc:HCO₂H (2:1 to 0:1) to give     pure white solid which is recrystallized from CHCl₃:hexane (3:1) to     give white crystals. ESI MS: m/z (rel intensity) 377.1 (M⁺+H, 100),     394.1 (M⁺+NH₃, 22).

Example 22

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carboxy-(4R)-hydroxy-pyrrolidine:     cis-Hydroxy-D-proline (10 g, 0.38 mole) is dissolved in     water:dioxane (1:1, 60 mL) with triethylamine (25 mL).     4-Methoxyphenylsulfonyl chloride (17.4 g, 0.084 mole) is added along     with 2,6-dimethylaminopyridine (0.92 g, 0.008 mole) and the mixture     is stirred 14 hr. at room temperature. The mixture is then     concentrated and diluted with EtOAc. Layers are separated and the     organic layer is washed 2× with 1N HCl, 1× with brine, dried over     MgSO₄, filtered and evaparated to give the title compound. ESI MS:     302.2 (M⁺+H, 100), 319.3 (M⁺+NH₄, 85). -   b. (1N)-4-Methoxyphenylsulfonyl-(2R)-carboxy-4-oxo-pyrrolidine: A     0.76 M batch of Jones' reagent is prepared. The carboxyalcohol 22a     (10.0 g, 31.7 mmoles) is dissolved in 175 mL of acetone and cooled     to 0° C. Jone's reagent is added (420 mL, 317 mmoles) and this is     stirred at room temperature for 14 hr. The reaction mixture is     diluted with water and extracted 3× with EtOAc. The organic layers     are washed 3× with water and 1× with sodium chloride, dried over     magnesium sulfate, and evaporated the material is recrystallized     from Hex:EtOAc to give the pure ketoacid. ESI MS: 300.3 (M⁺+H, 93),     317.3 (M⁺+NH₄, 100). -   d.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4,4)-(R)-hydroxy-ethylpyrrolidine:     The ketone 22b (0.500 g, 1.67 mmole) is taken in 10 mL of THF and     cooled to −15° C. Ethylmagnesium bromide (3.67 mL, 1M in THF, 3.67     mmole) is added to this mixture. The mixture is stirred for 30 min     at which time it is partitioned between 1N HCl and EtOAc. The     organic layer is washed with brine, dried over magnesium sulfate,     filtered and evaparated. The crude material is then stirred     overnight in methanol with 0.5 mL of SOCl₂ and evaparated to     dryness. The crude material is chromatographed over flash silica     with hex:EtOAc (1:1) to give the pure title compound. ESI MS: 363.3.     (M⁺+NH₄, 45), 346.3 (M⁺+H, 100). -   d.     (1N)-4-Methoxyphenylsulfonyl-(2R)-hydroxy-carboxamido-(4,4)-(R)-hydroxy-ethylpyrrolidine:     The methylester 22c (431 mg, 1.26 mmole) is taken in 1 mL of     methanol, treated with NH₂OK (2 mL, 0.86 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (2 mL) is added     to the mixture and the solvent removed under vaccuum. The dry silica     is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc:HCO₂H (2:1 to 0:1) to give     pure white solid which is recrystallized from CHCl₃:hexane (3:1) to     give white crystals. ESI MS: 362.2 (M⁺+NH₃, 60), 345.2 (M⁺+H, 100),     327.2 (15).

Example 23

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4,4)-(R)-gem-hydroxy-phenylpyrrolidine:     The keto acid 22b (441 mg, 1.47 mmole) is treated with     phenyl-magnesium bromide (3.7 mL, 3.7 mmole) as described for 22c to     give a black residue. This is then treated with K₂CO₃ (760 mg, 5.5     mmole) and MeI (0.343 mL, 5.5 mmole) in 10 mL of DMF for 45 min.     This mixture is then partitioned between EtOAc and brine. The     organic layer is then dried over MgSO₄, filtered and evaparated. The     crude residue is then chromatographed over flash silica with     hexane:EtOAc (9:1 to 7:3) to give the title compound as a brown oil.     CI⁺ MS: m/z (rel intensity) 409.4 (M+NH₄ ⁺, 100), 392.4 (M⁺+H, 75),     374.4 (65), 204.2 (72). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4,4)-(R)-gem-hydroxyphenylpyrrolidine:     The ester 23a (174 mg, 0.445 mmole) is converted to the title     hydroxamic acid as described for 22d. ESI MS: m/z (rel intensity)     410.6 (M+NH₄ ⁺, 100), 393.4 (M⁺+H, 75), 375.5 (65).

Example 24

-   a.     (N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(4-octyl)phenoxy     cyclobutylaine: Triphenylphosphine (2.5 g, 9.51 mmole) was dissolved     in 20 mL of THF, diethyl azodicarboxylate (1.9 mL, 9.51 mmole) was     added dropwise at 0° C. After 30 min with stirring., a solution of     4-octylphenol (2.46 g, 11.9 mmole) and the alcohol 1a (1.5 g, 4.76     mmole) in 20 mL of THF was added dropwise. The reaction was stirred     at 0° C. for 30 min., room temperature overnight and concentrated to     an oil. The crude product was s purified by flash chromatography     (hexane/EtOAc, 1:1) on silica gel to give the desired product. CI⁺     MS: m/z (rel intensity) 504 (44, M⁺+H), 334 (100). -   b.     (1N)-4-Methoxyphenylsulfonamido-(2R)-hydroxycarboxamido-(4S)-(4-octyl)phenoxy-pyrrolidine:     The methyl ester 24a (1.1 g, 2.1 mmole) was taken in 1 mL of     methanol, treated with NH₂OK (8 ml, 1.7 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred for 30 hr. Silica (1.5 mL) was added to the mixture and the     solvent was removed under vacuum. The dry silica was poured on the     top of a flash silica gel column which was subsequently eluted with     EtOAc:CH₃OH (95:5 to 90:10) to give 0.6 g (61% yield) of desired     product as a white foamy solid. ESI MS: m/z (rel intensity) 527 (30,     M⁺+Na), 522 (25, M⁺+NH₄), 505 (100, M⁺+H).

Example 25

-   a. (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-4-oxopyrrolidine:     A 0.76 M batch of jone's reagent was prepared. The alcohol 1a (10.0     g, 31.7 mmoles) was dissolved in 175 mL of acetone and cooled to     0° C. Jone's reagent was added (420 mL, 317 mmoles) and this was     stirred at room temperature for 14 hr. The reaction mixture was     diluted with water and extracted 3× with EtOAc. The organic layers     were washed 3× with water and 1× with sodium chloride, dried over     magnesium sulfate, and evaporated. Chromotography was performed on     silica gel using EtOAc:hexane (1:1) to give pure compound. Starting     material was also recovered. CI⁺ MS: m/z (rel intensity) 314.0     (M⁺+H, 100). -   b.     1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-3,3-dimethyl-4-oxopyrrolidine:     A solution of potassium bis(trimethylsilyl)amide (0.5 M, 10.2 mmole)     in 20.5 mL of toluene is cooled to 0° C. under argon atmosphere and     charged with 10 mL of     1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone. The mixture is     cooled to −78° C. A solution of the substrate 25a (800 mg, 2.56     mmole) in 20 mL of THF is then added dropwise and the resulting     mixture is stirred for 1 hr. Iodomethane (1.59 mL, 25.6 mmole) is     then added and the reaction is stirred at −78° C. and then     patitioned between EtOAc and dil. KHSO₄. The organic layer is then     washed with brine, dried over MgSO₄, filtered and evaperated. The     crude oil is then chromatographed over flash silica with hex:EtOAc     (3:1 to 1:1) to give the title compound. CI⁺ MS: m/z (rel intensity)     359 (M+NH₄ ⁺, 17), 342 (M⁺+H, 20), 172 (100). -   c.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-3,3-dimethyl-(4R)-hydroxypyrrolidine:     The starting ketone 25b (241 mg, 0.70 mmole) is taken in 5 mL of     methanol and treated with NaBH₄ (42 mg, 1.05 mmole) at room     temperature. The mixture is stirred at rt for 1 hr, quenced with 1N     HCl, and partitioned between 1N HCl and EtOAc. The mixture is then     partitioned between 1N HCl and EtOAc. The organic layer is washed     with brine, dried over MgSO₄, filtered and concentrated. The crude     oil is chromatographed over flash silica to give the title compound     as a clear syrup. The 1H NMR indicates a (10:1) diastereomeric     mixture. ESI MS: m/z (rel intensity): 346 (M⁺+H, 100), 363 (M⁺+NH₃) -   (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-3,3-dimethyl-(4R)-hydroxypyrrolidine:     The starting ester 25c (90 mg, 0.26 mmole) is converted to the title     compound as described for 22d. ESI MS: m/z (rel intensity): 345.2     (M⁺+H, 100), 362.2 (M⁺+NH₃), 65), 383.1 (M⁺+K, 55).

Examples 26-41

In the following examples W and Z are hydrogen, and Y is OH, n is 1, Ar is substituted or unsubstituted phenyl, and X and Q refer to substituents on the phenyl ring:

Example X Q Y 26 Me H a-OH 27 OMe 3-OMe a-OH 28 OMe 2-NO₂ a-OH 29 O(n-Bu) H a-OH 30 O(n-Bu) H b-OH 31 Br H a-OH 32 Br 3-Me a-OH 33 Cl 2-Cl a-OH 34 OCH₂CH₂OCH₃ H a-OH 35 OPh H a-OH 36 OCH(CH₃)₂ H a-OH 37 Br 2-Me b-S(3-C₆H₄OMe) 38 O(n-Bu) H b-2-mercaptobenzo-thiazole 39 OMe 2-NO₂ b-2-mercaptobenzo-thiazole 40 O(n-Bu) H b-S(4-C₆H₄OMe) 41 O(n-Bu) H O-(3-pyridyl) Me = methyl Et = ethyl Bu = butyl

Example 26

-   a.     (1N)-4-Methylphenylsulfonyl-(2R)-carbomethoxy-(4R)-hydroxy-pyrrolidine:     cis-Hydroxy-D-proline methylester (303 mg, 2.09 mmole) is dissolved     in DMF (3 mL) and N-methyl morpholine (1 mL) and stirred under air     for 14 hr at room temperature in the presence of p-toluenesulfonyl     chloride (418 g, 2.19 mmole). The mixture is then partitioned     between EtOAc and 1N HCl. The layers are separated and the organic     layer is washed 1× with 1N HCl, 1× with brine, dried over MgSO₄,     filtered and condensed to give 341 mg of crude material which is     chromatographed over flash silica with hexane:MeOH (19:1) to give     the desired material as a white solid. CI⁺ MS: m/z (rel intensity)     300 (M⁺+H, 60), 240 (28), 146 (88), 126 (100). -   b.     (1N)-4-Methylphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-hydroxy-pyrrolidine:     The methylester 26a (144 mg, 0.482 mmole) is taken in 1 mL of     methanol, treated with NH₂OK (0.61 mL, 0.86 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning the material is     concentrated and partitioned between EtOAc and 1N HCl. The organic     layer is washed with brine, dried over MgSO₄, filtered and     evaparated to give 134 mg of crude material which is chromatographed     over flash silica with EtOAc:MeOH (10:1) to give desired product     which is then recrystallized to give the desired white solid. ESI     MS: m/z (rel intensity) 301.0 (M+H⁺, 100), 318.0 (M+NH₄ ⁺, 35),     322.8 (M+Na⁺, 70).

Example 27

-   a.     (1N)-3,4-Dimethoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-hydroxy-pyrrolidine:     Cis-Hydroxy-D-proline methyl ester (2.71 g, 18.7 mmole) is dissolved     in DMF (10 mL) and N-methyl morpholine (5 mL) and stirred under air     for 14 hr at room temperature in the presence of     3,4-dimethoxyphenyl-sulfonyl chloride (4.65 g, 19.6 mmole). The     mixture is then partitioned between EtOAc and 1N HCl. The layers are     separated and the organic layer is washed 1× with 1N HCl, 1× with     brine, dried over MgSO₄, filtered and condensed to give 3.98 g of     crude material which is chromatographed over flash silica with     hexane:EtOAc (2:1 to 1:4) to give the desired material as a white     solid. CI⁺ MS: m/z (rel intensity) 346 (M⁺+H, 100), 286 (20), 146     (15). -   b.     (1N)-3,4-Dimethoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine:     The methylester 27a (250 mg, 0.724 mmole) is taken in 5 mL of     methanol, treated with NH₂OK (1.25 mL, 0.86 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (1.5 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (1:1 to 0:1) to give a white     foamy solid. ESI MS: m/z (rel intensity) 347.0 (M⁺+H, 100), 369.1     (M⁺+Na, 45).

Example 28

-   a.     (1N)-(2-Nitro-4-methoxyphenylsulfonyl)-(2R)-carbomethoxy-(4R)-hydroxypyrrolidine:     cis-Hydroxy-D-proline (3.02 g, 23.1 mmole) is dissolved in     water:dioxane (1:1, 300 mL) with triethylamine (7.9 mL, 57.5 mmole).     2-Nitro-4-methoxyphenylsulfonyl chloride (6.38 g, 25.4 mole) is     added along with 2,6-dimethylaminopyridine (281 mg, 2.31 mmole) and     the mixture is stirred 14 hr. at room temperature. The mixture is     then concentrated and diluted with EtOAc. Layers are separated and     the organic layer is washed 2× with 1N HCl, 1× with brine, dried     over MgSO₄, filtered and evaparated to give 7.06 g of solid material     which is dissolved in MeOH (100 mL). Thionyl chloride (10 mL) is     added dropwise and the resulting mixture stirred for 14 hr. The     mixture is then evaparated to dryness and triturated with CHCl₃ to     give a brownish solid which is sufficeintly pure to carry forward     without purification. CI⁺ MS: m/z (rel intensity) 378 (M+NH₄ ⁺, 40),     361 (M⁺+H, 100), 331 (12), 301 (43), 144 (95). -   b.     (1N)-(2-Nitro-4-methoxyphenylsulfonyl)-(2R)-N-hydroxy-carboxamido-(4R)-hydroxypyrrolidine:     The methylester 28a (300 mg, 0.833 mmole) is taken in 4 mL of     methanol, treated with NH₂OK (1.44 mL, 0.86 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (2 mL) is added     to the mixture and the solvent removed under vaccuum. The dry silica     is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (4:1) then with     EtOAc:MeOH:NH₄OH (8:2:0.1) to give a white solid. ESI MS: m/z (rel     intensity) 362.0 (M⁺+H, 100), 379.2 (M⁺+NH₄ ⁺, 7), 384.1 (M⁺+Na⁺,     55).

Example 29

-   a.     (1N)-(4-^(n)Butoxyphenylsulfonyl)-(2R)-carbomethoxy-(4R)-hydroxy-pyrrolidine:     Cis-D-Hydroxyproline methyl ester (583 mg, 4.02 mmole) is dissolved     in DMF (7 mL) and N-methyl morpholine (3 mL) and stirred under air     for 14 hr at room temperature in the presence of     para-n-butoxyphenylsulfonyl chloride (1.00 g, 4.02 mmole). The     mixture is then partitioned between EtOAc and 1N HCl. The layers are     separated and the organic layer is washed 1× with 1N HCl, 1× with     brine, dried over MgSO₄, filtered and condensed to give 1.2 g of     crude material which is chromatographed over flash silica with     hexane:EtOAc (4:1 to 1:3) to give the material as a white solid. CI⁺     MS: m/z (rel intensity) 358 (M⁺+H, 100), 298 (23), 146 (53), 114     (24). -   b.     (1N)-4-^(n)Butoxyphenylsulfonamido-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine:     The methylester 29a (347 mg, 0.971 mmole) is taken in 2 mL of     methanol, treated with NH₂OK (1.68 mL, 0.86 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (2 mL) is added     to the mixture and the solvent removed under vaccuum. The dry silica     is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (4:1) then with     EtOAc:MeOH:NH₄OH (4:1:0.1) to give a white solid. ESI MS: m/z (rel     intensity) 359.1 (M⁺+H, 100), 381.1 (M⁺+Na, 45).

Example 30

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-benzoyl-pyrrolidine:     The alcohol 29a (200 mg, 0.56 mmole) is dissolved in 1.5 mL of     methylene chloride. Benzoic acid (82 mg, 0.672 mmole) and triphenyl     phosphine (220 mg, 0.84 mmole) are then added, followed by diethyl     azodicarboxylate (106 mL, 0.672 mmole). After 3 hrs, the reaction     mixture is filtered and silica gel is added to the filtrate to     adsorb the solutes and the mixture is concentrated to dryness. The     resulting solid mixture is poured onto the top of a flash silica     column which is eluted with hex:EtOAc (3:1 to 2:1) to give the     desired product a white solid. CI⁺ MS: m/z (rel intensity) 479.1     (M+NH₄ ⁺, 55), 462.0 (M⁺+H, 30), 250.0 (100), 126 (38). -   b.     (1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-hydroxypyrrolidine:     The methylester 30a (154 mg, 0.334 mmole) is taken in 2 mL of     methanol, treated with NH₂OK (1.0 mL, 0.86 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (1.5 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (1:1 to 0:1) and finally with     EtOAc:MeOH:NH₄OH (9:1:0.1) to give a clear glassy solid. ESI MS: m/z     (rel intensity) 359 (M⁺+H, 40), 376 (M+NH₄ ⁺, 30), 381 (M+Na⁺, 20).

Example 31

-   a.     (1N)-4-Bromobenzenesulfonyl-(2R)-carbomethoxy-(4R)-hydroxypyrrolidine:     The title ester was prepared as described for compound 28a from     cis-hydroxy-D-proline (4.43 g, 35.1 mmole) and     4-bromobenzenesulfonyl chloride. ESI MS: m/z (rel intensity) 364.0     (M⁺+H, 95), 366.0 (M⁺+H, 95), 381.0 (M⁺+NH₃, 98), 383.0 (M⁺+NH₃,     100). -   b.     (1N)-4-Bromobenzenesulfonyl-(2R)-N-hydroxycarboxamido-(4R)-hydroxy-pyrrolidine:     The title hydroxamic acid was prepared from ester 31a (7.59 g, 20.9     mmole) as described for compound 25. The resulting material was     recrystallized from EtOAc. ESI MS: m/z (rel intensity) 365.1 (M⁺+H,     98), 367.1 (M⁺+H, 100), 382.2 (M+NH₄ ⁺, 45), 384.2 (M+N⁺, 45).

Example 32

-   a.     (1N)-2-Methyl-4-bromobenzenesulfonyl-(2R)-carbomethoxy-(4R)-hydroxypyrrolidine:     The title ester was prepared as described for compound 28a from     cis-hydroxy-D-proline (361 mg, 2.76 mmole) and     2-methyl-4-bromobenzenesulfonyl chloride. CI⁺ MS: m/z (rel     intensity) 397 (M⁺+NH₃, 100), 395 (M⁺+NH₃, 95), 380 (M⁺+H, 50), 378     (M⁺+H, 45), 317 (35), 300 (20), 146 (40). -   b.     (1N)-2-Methyl-4-bromobenzenesulfonyl-(2R)-hydroxycarboxamido-(4R)-hydroxypyrrolidine:     The title hydroxamic acid was prepared from ester 32a (271 mg, 0.72     mmole) as described for compound 28. The resulting material was     recrystallized from water. ESI MS: m/z (rel intensity) 398 (M⁺+NH₃,     85), 396 (M⁺+NH₃, 80), 379(M⁺+H, 90), 381 (M⁺+H, 100).

Example 33

-   a. (1N)-2,4-Dichloro-(2R)-carbomethoxy-(4R)-hydroxypyrrolidine: The     title compound is prepared as described for compound 28a from     cis-hydroxy-D-proline (500 mg, 3.8 mmole) and     2,4-dichlorobenzenesulfonyl chloride (1.03 g, 4.2 mmole). ESI MS:     m/z (rel intensity) 354.0 (M⁺+H, 100), 356.0 (M⁺+H, 73), 371.0     (M⁺+NH₄, 78), 373.0 (M⁺+NH₄ ⁺, 67). -   b.     (1N)-2,4-Dichloro-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine:     The title compound is prepared from ester 33a (550 mg, 1.55 mmole)     as described for compound 28b. ESI MS: m/z (rel intensity) 355.1     (M⁺+H, 100), 372.2 (M+NH⁺, 67).

Example 34

-   a. 4-(2-Methoxyethoxy)-phenylsulfonyl chloride: Methylsulfoxide (400     mL) is cooled with an ice/water bath with mechanical stirring and     charged with potassium hydroxide pellets (118.2 g, 2.11 mole)     followed by phenol (94.1 g, 0.70 mole) and then 2-bromoethylmethyl     ether (86 mL, 0.9 mole) is added at a rapid dripping rate. The     mixture is stirred for 15 min., warmed to room temperature and then     stirred for 2 hrs. It is then diluted with 1 L of ice/water and     extracted 2 times with CH₂Cl₂. The combined organic layers were then     dried over MgSO₄, filtered and evaparated The yield s in excess of     100% so it is taken in CHCl₃ and washed 2 times with water and 1     time with brine. This organic layer was processed similarly and the     concentrate was taken in 1.1 L of CH₂Cl₂ in a mechanically stirred     flask 5 L flask. Chlorosulfonic acid (140 mL, 2.1 mole) is added     dropwise causing slight warming A heavy precipitate is observed     after addition of half of the reagent, so the mixture is diluted     with 1.1 L of additional CH₂Cl₂. The resulting mixture is allowed to     stir at rt for 16 hrs. It is then poured onto −2 L of ice/water. The     layers are separated and the aqueous layer is extracted two times     with CH₂Cl₂. The combined organic layers are then combined, dried     over MgSO₄, filtered and evaparated to give the desired material     which is sufficiently pure to carry forward without purification.     ESI MS: m/z (rel intensity) 247.1 (M⁺+H, 35), 264.1 (M⁺+NH₃, 100),     269.0 (M⁺+Na, 45). -   b.     (1N)-4-(2-Methoxyethyl)phenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine:     The title compound is prepared as described for compound 28a. ESI     MS: m/z (rel intensity) 360.1 (M⁺+H, 85), 377.1 (M⁺+NH₄, 100). -   c.     (1N)-4-(2-Methoxyethyl)phenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine:     The starting methylester 34b (347 mg, 0.971 mmole) is stirred     overnight in 3 mL of methanol in the presence of NH₂OK (3.6 mL, 1.25     M in methanol, solution prepared as described in Fieser and Fieser,     Vol 1, p 478). The solution is then partitioned between 0.1 N HCl     and EtOAc. The organic layer is dried over MgSO₄, filtered and     evaparated to give 710 mg of a yellow solid which is chromatographed     over flash silica with EtOAc:MeOH (1:0 to 5:1) to give the title     compound which is puffed into a solid white foam under vacuum. ESI     MS: m/z (rel intensity) 361.1 (M⁺+H, 100), 378.1 (M⁺+NH₄,25).

Example 35

-   a.     (1N)-4-Phenoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-hydroxypyrrolidine:     The title compound is prepared fromcis-D-hydroxyproline (5.00 g,     38.1 mmole) and phenoxyphenylsulfonyl chloride (11.2 g, 42 mmole,     prepared as described for R. J. Cremlyn et al in Aust. J. Chem.,     1979, 32, 445.52) as described for compound 28a. The compound is     purified over flash silica with EtOAc:hexane (1:1 to 1:0) to give     the title compound as a clear gum. CI⁺ MS: m/z (rel intensity)     378.11 (M⁺+H, 100), 395.11 (M⁺+NH₃, 40). -   b.     (1N)-4-Phenoxyphenylsulfonyl-(2R)-N-hydroxycarhoxamido-(4R)-hydroxypyrrolidine:     The starting methyl ester 35a (864 mg, 2.30 mmole) is taken in 6 mL     of methanol:tetrahydrofuran (1:1), and treated with NH₂OK (3 mL,     1.25M in methanol) and stirred overnight. The following morning, dry     silica (1.5 mL) is added to the mixture and the solvent removed     under vacuum. The dry silica is poured on top of a flash silica     column which is subsequently eluted-with ethyl acetate followed with     ethyl acetate:methanol (8:2) to give a clear glass which is puffed     to a foamy solid by slight heating under vacuum. The product was     recrystallized from cold methanol to give the title compound as a     white powder. ESI MS: m/z (rel intensity) 379.10 (M⁺+H, 100),     396.10(M⁺+NH₃, 10).

Example 36

-   a. 4-(iso-butoxy)-phenylsulfonyl chloride: The title compound was     prepared as described for example 34a. ESI MS: m/z (rel intensity)     245.1 (M⁺+H, 50), 262.1 (M⁺+NH₃, 100). -   b.     (1N)-4-iso-butyloxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-hydroxypyrrolidine:     The title ester was prepared from cis-hydroxy-D-proline (10.0 g,     76.3 mmole) and sulfonyl chloride 36a (19.0 g, 76.3 mmole) as     described for compound 25a. ESI MS: m/z (rel intensity) 358.1 (M⁺+H,     100), 375.1 (M⁺+Na, 45). -   c.     (1N)-4-iso-butyloxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine:     The starting methyl ester 36b (1.5 g, 4.2 mmole) is taken in 7 mL of     methanol, and treated with NH₂OK (7 mL, 1.25M in methanol) and     stirred overnight. A precipitate formed which is filtered and     purified by partioning between water and EtOAc. The organic layer is     concentrated in vacuo and recrystallized from hexane:EtOAc to give     pure material. The original filtrate is dried and worked up like the     filtrate and filtered through dry silica gel with EtOAc:MeOH (9:1)     and the product was recrystallized from EtOAc:hexane to give     additional product. ESI MS: m/z (rel intensity) 359.1 (M⁺+H, 100),     376.1 (M⁺+NH₄, 55), 381.1 (M⁺+Na, 15).

Example 37

-   a.     1N)-2-Methyl-4-bromophenylsulfonyl-(2R)-carbomethoxy-(4S)-(3-methoxymercapto-phenyl)-pyrrolidine:     The starting alcohol 32a (310 mg, 0.82 mmole) is taken in 5 mL of     CH₂Cl₂ and 1 mL of triethylamine and treated with methanesulfonyl     chloride (76 μL, 0.984 mmole). The solution is stirred for 1 hr at     rt and then partitioned between EtOAc and 1N HCl. The organic layer     was dried over MgSO₄, filtered and evaparated. The crude residue was     then taken in 2.5 mL of THF at rt under argon and treated first with     ^(t)butoxide (50 mg, 0.45 mmole) and then 3-methoxythiophenol (110     μL, 0.90 mmole) The mixture is stirred for 16 hr and then     partitioned between EtOAc and 1N HCl. The organic layer is washed     with brine, dried over Na₂SO₄, filtered and evaparated to give a     residue which is then chromatographed over flash silica with     hexane:EtOAc (4:1) to give the title compound as a clear glass. CI⁺     MS: m/z (rel intensity) 517, 519 (M⁺+NH₃, 92), 500, 502 (M⁺+H, 48)     439 (30), 422 (20), 141 (50), 128 (100). -   b.     (1N)-2-Methyl-4-bromophenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(3-methoxymercapto-phenyl)-pyrrolidine:     The methylester 37a (101 mg, 0.202 mmole) is taken in 2 mL of     methanol:ThF (1:1), treated with NH₂OK (2.0 mL, 1.25 M in methanol,     solution prepared as described in Fieser and Fieser, Vol 1, p 478)     and stirred overnight. The following morning, dry silica (1.5 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with EtOAc and then with EtOAc:MeOH (4:1) to     give 79 mg (79%) of a clear glassy solid. ESI MS: m/z (rel     intensity) 501, 503 (M⁺+H, 65), 518, 520 (M⁺+NH₃, 100), 523, 525     (M⁺+Na, 35).

Example 38

-   a.     (1N)-^(n)Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(2-mercaptobenzothiazolyl)-pyrrolidine:     The alcohol 29a (200 mg, 0.56 mmole) is dissolved in 2.5 mL of     methylene chloride. 2-Mercaptobenzothiazole (113 mg, 0.672 mmole)     and triphenyl-phosphine (220 mg, 0.84 mmole) are then added,     followed by diethyl azodicarboxylate (106 mL, 0.672 mmole). After 3     hrs, the reaction mixture is filtered and silica gel is added to the     filtrate to adsorb the solutes and the mixture is concentrated to     dryness. The resulting solid mixture is poured onto the top of a     flash silica column which is eluted with hex:EtOAc (2:1 to 1:1) to     give the desired product. MS CI⁺ : m/z (rel intensity) 507.0     (M+H⁺,30), 359.1 (42), 342.0 (39), 167.9 (100), 135.9 (90). -   b.     (1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(2-mercapto-benzothiazolyl)-pyrrolidine:     The methylester 38a (214 mg, 0.422 mmole) is taken in 1.5 mL of     methanol, treated with NH₂OK (0.73 mL, 0.86 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (2 mL) is added     to the mixture and the solvent removed under vaccuum. The dry silica     is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (1:1 to 0:1) and finally with     EtOAc:MeOH:NH₄OH (4:1:0.1) to give a white powder. ESI MS: m/z (rel     intensity) 508 (M⁺+H. 100), 532 (M⁺+Na, 32).

Example 39

-   a.     (1N)-2-Nitro-4-methoxyphenylsulfonyl-(2R)-N-carbomethoxy-(4S)-(2-mercapto-benzothiazolyl)-pyrrolidine:     The alcohol 28a (200 mg, 0.55 mmole) is dissolved in 1.5 mL of     methylene chloride. 2-Mercaptobenzothiazole (112 mg, 0.66 mmole) and     triphenyl phosphine (219 mg, 0.833 mmole) are then added, followed     by diethyl azodicarboxylate (105 mL, 0.666 mmole). After 3 hrs, the     reaction mixture is filtered and silica gel is added to the filtrate     to adsorb the solutes and the mixture is concentrated to dryness.     The resulting solid mixture is poured onto the top of a flash silica     column which is eluted with hex:EtOAc (4:1 to 1:1) to give the     desired product as a white solid. CI⁺ MS: m/z (rel intensity) 509.9     (M⁺+H, 30), 315.0 (18), 294.9 (18), 167.9 (100), 135.9 (95). -   b.     (1N)-2-Nitro-4-methoxyphenylsulfonyl-(2R)-N-hydroxy-carboxamido-(4S)-(2-mercapto-benzothiazolyl)-pyrrolidine:     The methylester 39a (277 mg, 0.544 mmole) is taken in 1 mL of     methanol, treated with NH₂OK (1.0 mL, 0.86 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (2 mL) is added     to the mixture and the solvent removed under vaccuum. The dry silica     is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (1:1 to 0:1) followed by     EtOAc:MeOH:NH₄OH (9:1:0.1) to give the white solid. ESI MS: m/z (rel     intensity) 511.1 (M⁺+H, 100), 533.0 (M⁺+Na, 30).

Example 40

-   a.     (1N)-(4-^(n)butoxyphenylsulfonyl)-(2R)-carbomethoxy-(4S)-(4-methoxymercaptophenyl)-pyrrolidine:     The alcohol 29a (178 mg, 0.499 mmole) is taken in 2 mL of CH₂Cl₂ and     to this mixture is added triphenylphosphene (157 mg, 0.599 mmole),     4-methoxythiophenol (67 mL, 0.548 mmole), and     diethyl-diazadicarboxylate (95 mM, 0.0.548 mmole) and the mixture is     stirred for 3 hr. at which time 3 mL of silica gel is added to the     mixture which is then concentrated to dryness. The dry residue is     poured onto the top of a flash silica column and eluted with     hexane:EtOAc (4:1 to 1:4) to give a clear oil. CI⁺ MS: m/z (rel     intensity) 468 (M⁺+H, 48), 301 (43), 272 (46), 187 (65), 109 (100). -   b.     (4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-(4-methoxyphenyl-thioloxy)-pyrrolidine:     The methylester 40a (125 g, 0.268 mmole) is taken in 1 mL of     methanol, treated with NH₂OK (0.465 mL, 0.86 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (2 mL) is added     to the mixture and the solvent removed under vaccuum. The dry silica     is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (2:1 to 0:1) to give a white     solid. ESI MS: m/z (rel intensity) 481 (M⁺+H, 10), 498.1 (M+NH₄ ⁺,     100), 503.1 (M⁺+Na, 20).

Example 41

-   a.     (1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(3-pyridyloxy)-pyrrolidine:     The title compound is prepared as described for 13a. CI⁺ MS: m/z     (rel intensity) 468 (M⁺+H, 48), 301 (43), 272 (46), 187 (65), 109     (100). -   a.     (1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(3-pyridyloxy)-pyrrolidine:     The title compound is prepared as described for 13b. ESI MS: m/z     (rel intensity) 436.1 (M⁺+H, 100), 458.1 (M+NH₄ ⁺, 60), 517.8     (M⁺+Na, 15).

Examples 42-61

In the following examples W and Z are hydrogen, and Y is OH, n is 1, Ar is substituted or unsubstituted phenyl, and X and Q refer to substituents on the phenyl ring:

Example X P R 42 OMe H H 43 OnBu H H 44 OMe H n-Pr 45 OMe H n-Hex 46 OMe H CH₂CH₂Ph 47 OMe n-Bu n-Hex 48 OMe H SO₂Me 49 On-Bu H SO₂Me 50 On-Bu H SO₂3-(N- methylimidazole) 51 OMe CH₂(3- SO₂Me pyridyl) 52 OMe SO₂Me SO₂Me 53 OMe n-Pr SO₂Me 54 OMe H SO₂pC₆H₄OMe 55 OMe H COn-Pent 56 OMe H COp-Ph—Ph 57 OMe H CONHMe 58 OMe H COCH(R—OBn)CH₃ 59 OMe H COCH(R—OBn)CH₂Ph 60 OMe i-Pr COCH(R—OH)CH₃ 61 OMe i-Pr COCH(R—OH)CH₂Ph

Example 42

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-azidopyrrolidine:     The starting mesylate 15a (4.2g, 10.7 mmole) is taken in 15 mL of     dry DMF in the presence of NaN₃ (695 mg, 10.7 mmole). The resulting     mixture is heated to 55° C. for 26 hrs and then partitioned between     water and EtOAc. The organic layer is then washed with brine, dried     over MgSO₄, filtered and evaparated. The resulting crude oil is     chromatographed over flash silica with hexane:EtOAc (5:1 to 3:1) to     provide pale yellow oil which solidifies upon standing. CI⁺ MS: m/z     (rel intensity) 358 (M+NH₄ ⁺, 50), 341 (M⁺+H, 67), 315 (95), 145     (100). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-aminopyrrolidine:     The starting azide 42a (1.18 g, 3.48 mmole), is taken in 100 mL of     EtOH:THF:HCO₂H (5:1:0.1), and hydrogenated at rt. under 54 psi of     hydrogen in the presence of 100 mg of 10% Pd-C for 16 hrs. The     mixture is then filtered through a pad of celite, concentrated to an     oil and recrystallized from hexane:EtOAc to give the desired product     as the formate salt. CI⁺ MS: m/z (rel intensity) 315 (M⁺+H, 12), 177     (13), 143 (42), 123 (60), 109 (100). -   c.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-aminopyrrolidine:     The starting ester 42b (500 mg, 1.59 mmole), is taken in 5 mL of     MeOH, treated with NH₂OK (1.92 mL, 0.86 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (1.5 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with EtOAc:MeOH (4:1 to 3:2) to give white     solid. ESI MS: m/z (rel intensity) 316.3 (M⁺+H, 100), 333.3 (M⁺+NH₄,     15).

Example 43

-   a.     (1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-methylsulfonoxy-pyrrolidine:     The starting alcohol 1a (6.78 g, 19.0 mmole) is converted to the     title mesylate as described for compound 15a. CI MS: m/z (rel     intensity) 453 (M+NH⁺, 38), 336 (M⁺+H, 27), 224 (100), 128 (67). -   b.     (1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-azidopyrrolidine:     The starting mesylate 43a (5.85 g, 13.5 mmole) is converted to the     tide azide as described for compound 41a. ESI MS: m/z (rel     intensity) 383.1 (M⁺+H, 50), 400.1 (M⁺+NH₃, 100) -   c.     (1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-aminopyrrolidine:     The starting azide 43b (4.65 g, 12.2 mmole), is taken in 200 mL of     MeOH with 20 mL of HOAc and hydrogenated at rt. under 54 psi of     hydrogen in the presence of 200 mg of 10% Pd-C for 16 hrs. The     mixture is then filtered through a pad of celite, concentrated to an     oil, taken in MeOH and stirred with ˜50 g of Amberlite IRA-68 basic     resin (preconditioned with 0.1 N NaOH, water and MeOH), filtered     through a glass frit and adsorbed onto a plug of silica. This is     then eluted over a column of flash silica with EtOAc:MeOH (1:0 to     3:1) to give pale yellow oil which solidifies upon standing. CI MS:     m/z (rel intensity) 357 (M⁺+H, 65), 145 (100). -   d.     (1N)-4-Methoxyphenylsulfonyl-(2R)-hydroxycarboxamido-(4S)-amino-pyrrolidine:     The starting ester 43c (234 mg, 356 mmole), is converted to the     title compound as described for compound 42c and then purified     further by recrystallizing from water to give white crystalls. ESI     MS: m/z (rel intensity) 358 (M⁺+H).

Example 44

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-propylamino-pyrrolidine:     The starting amine 42b (810 mg, 2.6 mmole) is dissolved in 8 mL of     methanol and stirred for 48 hrs in the presence of propianaldehyde     (206 mL, 2.86 mmole), sodium cyanoborohydride (180 mg, 2.86 mmole),     sodium acetate (810, 9.9 mmole) and 25 drops of acetic acid. The     mixture is evaparated to dryness and then partitioned between dil.     NaHCO₃ and EtOAc and the organic layer is washed 2 times with     NaHCO₃, 1 time with brine, dried over MgSO₄, filtered and evaparated     to give a gummy oil which was sufficiently clean to carry forward     without further purification. ESI MS: m/z (rel intensity) 357.3     (M⁺+H, 100). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-propylamido-pyrrolidine:     The starting methylester 44a (11.3, g, 31.7 mmole) is taken in 30 mL     of methanol, treated with NH₂OK (38 mL, 1.25 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred for 16 hrs. The following morning, dry silica (30 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with chloroform:methanol (8:2) to give a pale     yellow solid which was taken in methanol and stirred for 1 hr in the     presence of activated charcoal and then filtered through celite and     evaparated to give a white solid. ESI MS: m/z (rel intensity) 358.2     (M⁺+H, 100), 380.1 (M⁺+Na, 5).

Example 45

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-^(n)hexylamino-pyrrolidine:     The starting alcohol 1a (300 mg, 0.951 mmole) is dissolved in 2 mL     of CH₂Cl₂ under argon and cooled to 0° C. 2,6-Lutidine (135 μL, 1.14     mmole) is added via syringe followed by like addition of     trifluoro-methanesulfonyl anhydride (179 mL, 1.05 μmole). The     mixture is stirred for 1 hr., followed by syringe addition of dry     hexylamine (500 μL, 3.80 mmol) and then the mixture is allowed to     come to room temperature, stir for 14 hrs., and heat to reflux for 4     hrs. Silica gel (3 mL) is added and the mixture evaparated to     dryness. The dry powder is poured on the top of a column of flash     silica gel which is then eluted with hexane:EtOAc (2:1Ø1:1) to give     a colorless, glassy solid. CI⁺ MS: m/z (rel intensity) 399 (M⁺+H,     38), 229 (100), 227 (62). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(^(n)hexylamino)-pyrrolidine:     The starting methylester 45a (88 mg, 0.221 mmole) is taken in 1 mL     of methanol, treated with NH₂OK (0.381 mL, 0.86 M in methanol,     solution prepared as described in Fieser and Fieser, Vol 1, p 478)     and stirred overnight. The following morning, dry silica (1.5 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (1:1Ø0:1) to give a white     foamy solid. ESI MS: m/z (rel intensity) 400.3 (M⁺+H, 100), 422.2     (M⁺+Na, 12).

Example 46

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-2-phenylethyl-aminopyrrolidine:     The primary amine 42b (300 mg, 1 mmole) is N-alkylated with     phenylacetaldehyde (0.13 mL, 1.1 mmole) as described for compound     44a to give the desired amine as a clear gum which was carried     forward without further purification. CI⁺ MS: m/z (rel intensity)     419 (M⁺+H, 38), 249 (20), 249 (19). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-2-phenylethyl-aminopyrrolidine:     The starting ester 46a (490 mg, 1 mmole) is converted to the title     compound as described for compound 45b and purified over flash     silica with EtOAc:MeOH (4:1) to give a white solid. ESI MS: m/z (rel     intensity) 420.4 (M⁺+H, 100).

Example 47

-   a     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N,N-^(n)butyl,^(n)hexylamino-pyrrolidine:     The starting amine 45a (100 mg, 0.251 mmole) was converted to 93 mg     (82%) of the title compound as described for compound 44a. CI⁺ MS:     m/z (rel intensity) 470 (M⁺+H, 10), 299 (20), 242 (100). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-N,N-^(n)butyl,^(n)hexylamino-pyrrolidine:     The starting ester 47a (80.5 mg, 0.172 mmole) was converted to 56 mg     (69%) of the title compound as described for compound 44b. CI⁺ MS:     m/z (rel intensity) 469 (M⁺+H, 42), 299 (100), 242 (28), 172 (46).

Example 48

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-methanesufonyl-amino-pyrrolidine:     The primary amine 42b (502 mg, 1.60 mmole) is taken in 5 mL of     methylene chloride and 0.5 mL of triethyl amine and treated with     methanesulfonyl chloride (200 μL, 2.58 mmole) via syringe. The     mixture is stirred for 2 hr and then partitioned between 1N HCl and     EtOAc. The organic layer was washed with brine, dried over MgSO₄,     filtered and evaparated to give 684 mg of crude material which was     chromatographed over flash silica with hexane:EtOAc (2:1 to 1:1) to     give disulfonylated material 51a and monosulfonylated material 47a.     CI⁺ MS: m/z (rel intensity) 410 (M⁺+NH₄, 15), 393 (M⁺+H, 10), 203     (100). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-hydroxycarboxamido-(4S)-methane-sulfonylaminopyrrolidine:     The starting ester 48a (354 mg, 0.903 mmole) is converted to the     title compound and chromatographed as described for compound 45b. It     is then recrystallized from acetonitrile/water to give pale yellow     crystalls. ESI MS: m/z (rel intensity) 394 (M⁺+H, 60), 411 (M⁺+NH₄,     100).

Example 49

-   a.     (1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-methanesulfonyl-aminopyrrolidine:     The primary amine 43c (21.3 g, 60 mmole) is taken in 120 mL of     methylene chloride and 36 mL of triethyl amine and treated dropwise     with methanesulfonyl chloride (5.1 mL, 66 mmole) at 0° C. The     mixture is allowed to come to room temperature for 1 hr and then     adsorbed onto silica, evaparated to dryness, and eluted through a     column of flash silica with hexane:EtOAc (4:1 to 1:1) to give the     titde compound. ESI MS: m/z (rel intensity) 452 (M⁺+NH₃, 12), 435     (M⁺+H, 9), 223 (100). -   b.     (1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-methane-sulfonyl-aminopyrrolidine:     The starting ester 49a (21.4 g, 49.2 mmole) is taken in 60 mL of     methanol:THF (1:1), treated with NH₂OK (59 mL, 1.25 M in methanol,     solution prepared as described in Fieser and Fieser, Vol 1, p 478)     and stirred overnight. The following morning, dry silica (45 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (1:1Ø0:1), then EtOAc:methanol     (9:1) to give a white foamy solid. This material was heated to     60° C. for 48 hrs and a white, solid impurity sublimed off leaving     behind light yellow powder. ESI MS: m/z (rel intensity) 453.08     (M⁺+NH₃, 50), 436.05 (M⁺+H, 100).

Example 50

-   a.     (1N)-4-n-Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-[(1N)-methyl-3-imidazolyl]-sulfonylamino-pyrrolidine:     The primary amine 43c (232 mg, 0.906 mmole) is taken in 3 mL of     methylene chloride and 0.5 mL of triethyl amine and treated with     1N-methyl-3-imidazoyl-sulfonyl chloride (280 mg, 1.55 mmole) at rt.     The mixture is allowed to stir for 16 hr and then adsorbed onto     silica, evaparated to dryness, and eluted through a column of flash     silica with hexane:EtOAc (1:1 to 0:1) to give the title compound as     a clear oil which contained −20 mole percent of the starting     sulfonyl chloride. This material was carried forward without further     purification. ESI MS: m/z (rel intensity) 501 (M⁺+H, 70), 357 (45),     289 (82), 162 (100). -   b.     (1N)-4-n-Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-[(1N)-methyl-3-imidazolyl]-sulfonylamino-pyrrolidine:     The starting ester 50a (236 mg, 0.471 mmole) is converted to the     tide compound and chromatographed as described for compound 45b to     give 262 mg of yellow oil which was further purified by reverse     phase prep. HPLC to give pure solid. ESI MS: m/z (rel intensity)     502.2 (M⁺+H).

Example 51

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(3-pyridyl)-methyl-aminopyrrolidine:     The primary amine 42b (810 mg, 2.6 mmole) is N-alkylated with     3-pyridine-carboxaldehyde (270 μL, 2.86 mmole) as described for     compound 44a to give the desired amine as a clear gum which is     purified over flash silica gel with EtOAc:MeOH (1:0 to 9:1) to give     white solid. CI MS: m/z (rel intensity) 406 (M⁺+H, 100), 236 (45),     234 (48). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N,N-(3-pyridylmethyl)-(methanesulfonyl)-aminopyrrolidine:     The secondary amine 51a (7.80 mg, 19.3 mmole) is taken in 85 mL of     methylene chloride and 11 mL of triethyl amine with a catalytic     amount of 2,5-dimethylamino-pyridine and treated with     methanesulfonyl chloride (4.5 mL, 57.8 mmole) at rt. The mixture is     allowed to stir for 16 hr and then adsorbed onto silica, evaparated     to dryness, and eluted through a column of flash silica with     EtOAc:MeOH (0:1 to 9:1) to give the title compound as a yellow foamy     solid. CI MS: m/z (rel intensity) 484 (M⁺+H, 30), 406 (10), 314     (40), 234 (90), 187 (42), 102 (100). -   c.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-N,N-(3-pyridylmethyl)-(methanesulfonyl)-aminopyrrolidine:     The starting ester 51b (6.33 g, 13.1 mmole) is converted to the     relative hydroxamic acid as described for compound 45b and eluted     through flash silica with EtOAc:MeOH (1:0 to 4:1) to give the tide     compound as a white powder. ESI MS: m/z (rel intensity) 484.9 (M⁺+H,     100), 506.9 (M⁺+NH₃, 10).

Example 52

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-bis-(N-methanesulfonyl)-amino-pyrrolidine:     The title compound is isolated from the crude mixture in 48a. ESI     MS: m/z (rel intensity) 488.3 (M⁺+NH₄ ⁺, 15), 471.3 (M⁺+H, 10). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-bis-(N-methanesulfonyl)-amino-pyrrolidine:     The starting ester 52a (94 mg, 0.20 mmole) is converted to the     relative hydroxamic acid as described for compound 48b and eluted     through flash silica with EtOAc:MeOH (1:0 to 5:1) to give the tide     compound as a white solid. ESI MS: m/z (rel intensity) 489.3 (M⁺+NH₄     ⁺, 55), 472.3 (M⁺+H, 100).

Example 53

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(methane-sulfonyl)-propyl-aminopyrrolidine     The starting amine 44a (783 mg, 2.20 mmole) was converted to the     tide compound as described for 48a. ESI MS: m/z (rel intensity) 452     (M+NH₄ ⁺), 435 (M⁺+H, 75), 265 (100), 155 (75), 126 (40). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-N-(methanesulfonyl)-propyl-aminopyrrolidine     The starting ester 53a (614 mg, 1.41 mmole) was converted to the     tide compound as described for 48b. ESI MS: m/z (rel intensity)     452.9 (M+NH₄ ⁺, 100), 435.8 (M⁺+H, 55).

Example 54

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-4-methoxyphenyl-sulfonylamino-pyrrolidine:     The primary amine 42b (400 mg, 1.27 mmole) is converted to the tide     compound with p-methoxybenzenesulfonyl chloride (316 mg, 1.53 mmole)     as described for compound 48a. CI⁺ MS: m/z (rel intensity) 502     (M⁺+NH₄ ⁺, 12), 485 (M⁺+H, 10), 315 (100). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-4-methoxyphenyl-sulfonylamino-pyrrolidine:     The starting ester 54a (480 mg, 0.99 mmole) is converted to the     relative hydroxamic acid as described for compound 48b and eluted     through flash silica with EtOAc:MeOH:HCO₂H (1:0:0 to 4:1:0.1) to     give the tide compound as a white solid which was recrystallized     from acetonitrile:water to give white crystalls. ESI MS: m/z (rel     intensity) 486 (M⁺+H, 100), 503 (M⁺+NH₄, 30).

Example 55

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(-1-oxyhexyl)-aminopyrrolidine:     The primary amine 42b (500 mg, 1.59 mmole) is converted to the tide     compound with hexanoyl chloride (268 μL, 1.91 mmole) as described     for compound 48a. ESI MS: m/z (rel intensity) 413.2 (M⁺+H, 70),     430.2 (M⁺+NH₄, 100). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(-1-oxyhexyl)-aminopyrrolidine:     The starting ester 55a (560 mg, 1.35 mmole) is converted to the     relative hydroxamic acid as described for compound 48b and eluted     through flash silica with EtOAc:MeOH:HCO₂H (1:0:0 to 4:1:0.1) to     give the tide compound as a pale orange, viscous sap which would not     solidify. ESI MS: m/z (rel intensity) 431.4 (M⁺+NH₄ ⁺, 25), 414.4     (M⁺+H, 35), 102 (100).

Example 56

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-p-biphenylyl-aminopyrrolidine:     The primary amine 42b (1.00 g, 3.19 mmole) is converted to the title     compound with 4-biphenyl chloride (761 mg, 3.51 mmole) as described     for compound 48a. CI⁺ MS: m/z (rel intensity) 4.95 M⁺+H, 30), 325     (100), 198 (55), 155 (27). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-hydroxycarboxamido-(4S)-p-biphenylylaminopyrrolidine:     The starting ester 56a (200 mg, 0.404 mmole) is converted to the     relative hydroxamic acid as described for compound 48b and eluted     through flash silica with EtOAc:MeOH(1:0:0 to 9:1) to give 129 mg     (65%) of the title compound. ESI MS: m/z (rel intensity) 496.0     (M⁺+H, 100), 513.0 (M+NH₄ ⁺, 60), 517.8 (M⁺+Na, 15).

Example 57

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-methylcarboxamyl-aminopyrrolidine:     The primary amine 42b (470 mg, 1.49 mmole) is taken in 4 mL of     dioxane with 1 mL of triethyl amine and a catalytic amount of DMAP     and then treated with methyl isocyanate (106 mL, 1.80 mmole) and     stirred for 16 hrs at rt. The mixture is then partitioned between     EtOAc and 1N HCl and the organic layer is washed with brine, dried     over MgSO₄, filtered and evaparated. The residue is then     chromatographed over flash silica with hexane:EtOAc (1:2 to 0:1) to     give white solid. CI⁺ MS: m/z (rel intensity) 389 (M⁺+NH₄ ⁺, 5), 372     (M⁺+H, 25), 202 (100). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-hydroxycarboxamido-(4S)-methyl-carboxamyl-aminopyrrolidine:     The starting ester 57a (351 mg, 0.95 mmole) is converted to the     relative hydroxamic acid as described for compound 48b and eluted     through flash silica with EtOAc:MeOH (8:1) to give the tide compound     as a white solid which was recrystallized from acetonitrile:water to     give white crystalls. ESI MS: m/z (rel intensity) 411.0 (M⁺+K, 30),     373.1 (M⁺+H, 100), 316 (32).

Example 58

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(1-oxo-2R-benzyloxy-propyl)-aminopyrrolidine:     The starting amine 42b (465 mg, 1.48 mmole), and the starting     L-o-benzyllactic acid (319 mg, 1.78 mmole) is taken in 4 mL of DMF     in the presence of 1.5 mL of N-methylmorpholine, EDAC (568 mg, 2.96     mmole) and HOBT (599 mg, 4.44 mmole). The resulting mixture is     stirred at rt for 16 hr and then partitioned between 1N HCl and     EtOAc. The organic layer is then washed 1× with dil NaHCO₃, 1× with     brine, dried over MgSO₄, filtered and evaparated. The crude residue     is then chromatographed with hexane:EtOAc (2:1 to 1:3) to give the     title compound. ESI MS: m/z (rel intensity) 477.2 (M⁺+H, 100), 494.2     (M⁺+NH₃, 10). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-N-(1-oxo-2R-benzyloxypropyl)-aminopyrrolidine:     The starting methylester 58b (480 mg, 1.01 mmole) is taken in 2 mL     of methanol, treated with NH₂OK (2.5 mL, 1.25 M in methanol,     solution prepared as described in Fieser and Fieser, Vol 1, p 478)     and stirred overnight. The following morning, dry silica (3 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with EtOAc:MeOH (1:0Ø4:1) to give 338 mg (70%)     of a white foamy solid. ESI MS: m/z (rel intensity) 478.3 (M⁺+H,     100), 500.2 (M⁺+Na, 12).

Example 59

-   a. 2R-benzyloxy-3-phenylproionic acid: Sodium hydride (2.9 g, 120     mmole), is washed 2 times with hexane and covered with 50 mL of DMF.     The starting L-3-phenyllactic acid (5 g, 30.1 mmole) is then added     in portions and, after fizzing ceased, the mixture is heated to     55° C. for 1 hr. The mixture is then cooled to 0° C. and benzyl     bromide (4.3 mL, 36.1 mmole) is added dropwise. The mixture is     heated to 60° C. for 3 hr and then partitioned between hexane:EtOAc     (1:1) and 1N HCl. The organic layer is washed with brine, dried over     MgSO₄, filtered and evaparated. The residue is chromatographed over     flash silica with hexane:EtOAc (9:1 to 0:1) to give a colorless oil.     ESI MS: m/z (rel intensity) 274.3 (M⁺+NH₃, 100). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(1-oxo-2R-benzyloxy-3-phenylpropyl)-aminopyrrolidine:     The starting amine 44a (800 mg, 2.55 mmole), and the starting benzyl     lactic acid 59a (784 mg, 3.06 mmole) is taken in 5 mL of DMF in the     presence of 1 mL of N-methylmorpholine, EDAC (979 mg, 5.10 mmole)     and HOBT (1.03 mg, 7.65 mmole). The resulting mixture is stirred at     rt for 16 hr and then partitioned between 1N HCl and EtOAc. The     organic layer is then washed 1× with dil NaHCO₃, 1× with brine,     dried over MgSO₄, filtered and evaparated. The crude residue is then     chromatographed with hexane:EtOAc (8:1 to 1:1) to give the title     compound. ESI MS: m/z (rel intensity) 553.2 (M⁺+H, 100), 570.3     (M⁺+NH₃, 18). -   c.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-N-(1-oxo-2R-benzyloxy-3-phenylpropyl)-aminopyrrolidine:     The starting methylester 59b (700 mg, 1.27 mmole) is taken in 2 mL     of methanol, treated with NH₂OK (2.5 mL, 1.25 M in methanol,     solution prepared as described in Fieser and Fieser, Vol 1, p 478)     and stirred overnight. The following morning, dry silica (3 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica-gel column which is     subsequently eluted with hexane:EtOAc (1:1Ø0:1) to give a white     foamy solid. ESI MS: m/z (rel intensity) 553.3 (M⁺+H, 100), 576.3     (M⁺+Na, 23).

Example 60

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(1-oxo-2R-benzyloxy-propyl)-propyl-aminopyrrolidine:     The starting amine 44a (636 mg, 1.79 mmole), and the starting     L-o-benzyllactic acid (390 mg, 2.15 mmole) is taken in 5 mL of DMF     in the presence of 1 mL of N-methylmorpholine, EDAC (687 mg, 3.58     mmole) and HOBT (762 mg, 5.37 mmole). The resulting mixture is     stirred at rt for 16 hr and then partitioned between 1N HCl and     EtOAc. The organic layer is then washed 1× with dil NaHCO₃, 1× with     brine, dried over MgSO₄, filtered and evaparated. The crude residue     is then chromatographed with hexane:EtOAc (8:1 to 1:1) to give the     title compound. ESI MS: m/z (rel intensity) 595.2 (M⁺+H, 100). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(1-oxo-2R-hydroxy-propyl)-propyl-aminopyrrolidine:     The starting ether 60a (700 mg, 1.35 mmole) is taken in 25 mL of     methanol with catalytic 10% Pd-C and H₂SO₄ and hydrogenated for 3     hrs at 54 psi in a Parr apparatus. The material is then filtered     through a pad of celite,evaparated to dryness and chromatographed     over flash silica to give a clear gum. ESI MS: m/z (rel intensity)     429.3 (M⁺+H, 100), 446.3 (M⁺+NH₃, 12). -   c.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(1-oxo-2R-hydroxypropyl)-propyl-aminopyrrolidine:     The starting methylester 60b (331 mg, 0.771 mmole) is taken in 1 mL     of methanol, treated with NH₂OK (1.23 mL, 1.25 M in methanol,     solution prepared as described in Fieser and Fieser, Vol 1, p 478)     and stirred overnight The following morning, dry silica (3 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (1:1Ø0:1) to give a white     foamy solid. ESI MS: m/z (rel intensity) 519.3 (M⁺+H, 100), 536.3     (M⁺+NH₃, 60).

Example 61

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N,N-(1-oxo-2R-benzyloxy-3-phenylpropyl)-propyl-aminopyrrolidine:     The acid 59a (530 mg, 1.68 mmole) was taken in 15 mL of CH₂Cl₂ and     treated with oxalyl chloride (293 μL, 3.37 mmole). A catalytic drop     of DMF was added and the mixture was stirred for a total of 3.5 hrs     and then evaparated to dryness. The residue was taken in 15 mL of     CH₂Cl₂ and added to a solution of the starting amine 44a (449 mL,     1.26 mmole) in 10 mL of CH₂Cl₂ and 2 mL of triethyl amine. The     resulting solution was stirred for 16 hrs. and then partitioned     between EtOAc and 1 N HCl. The organic layer was washed 1 time with     1 N HCl, 2 times with NaHCO₃, 1 time with brine, dried over MgSO₄,     filtered and evaparated to give 740 mg of crude gum. This is then     chromatographed over flash silica with hexane:EtOAc (4:1 to 1:2) to     give a pale yellow gum. ESI MS: m/z (rel intensity) 595.2 (M⁺+H,     100) -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(1-oxo-2R-hydroxy-3-phenylpropyl)-propyl-aminopyrrolidine:     The starting ether 61a (480 mg, 0.807 mmole) is taken in 20 mL of     methanol with catalytic 10% Pd-C and H₂SO₄ and hydrogenated for 16     hrs at 50 psi in a Parr apparatus. The material is then filtered     through a pad of celite,evaparated to dryness and chromatographed     over flash silica with EtOAc to give a clear gum. ESI MS: m/z (rel     intensity) 505.3 (M⁺+H, 100), 522.3 (M⁺+NH₃, 15). -   c.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-N-(1-oxo-2R-hydroxy-3-phenylpropyl)-propyl-aminopyrrolidine:     The starting methylester 61b (307 mg, 0.608 mmole) is taken in 1 mL     of methanol, treated with NH₂OK (1.23 mL, 1.25 M in methanol,     solution prepared as described in Fieser and Fieser, Vol 1, p 478)     and stirred overnight. The following morning, dry silica (3 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with hexane:EtOAc (1:1Ø0:1) to give a white     foamy solid. ESI MS: m/z (rel intensity) 506.3 (M⁺+H, 100), 526.3     (M⁺+Na, 12).

Examples 62-63

In the following examples W and Z are hydrogen, and Y is OH, n is 1, Ar is substituted or unsubstituted phenyl, and X and Q refer to substituents on the phenyl ring:

Example X Y 62 OMe CH₂ 63 OnBu CH₂ 64 OMe O 65 OnBu O 66 OMe SO₂ 67 OnBu SO₂

Example 62

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1-piperidyl-pyrrolidine:     The starting amine 42b (1.00 g, 3.19 mmole) is dissolved in 10 mL of     methanol and stirred for 16 hrs in the presence of glutonic     dialdehyde (961 mg, 50 wt % in water, 4.8 mmole), sodium     cyanoborohydride (503 mg, 8 mmole), sodium acetate (1 g) and 1 mL of     acetic acid. The mixture is evaparated to dryness and then     partitioned between dil. NaHCO₃ and EtOAc and the organic layer is     washed 2 times with NaHCO₃, 1 time with brine, dried over MgSO₄,     filtered and evaparated to give a clear colorless glass which is     chromatographed over flash silica with hexane:EtOAc (4:1 to 1:1) to     give the desired product as a glear glass. ESI MS: m/z (rel     intensity) 383 (M⁺+H, 100), 211 (38). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1-piperidyl-pyrrolidine:     The starting methylester 62a (1.00 g, 2.62 mmole) is taken in 3 mL     of methanol, treated with NH₂OK (4 mL, 1.25 M in methanol, solution     prepared as described in Fieser and Fieser, Vol 1, p 478) and     stirred overnight. The following morning, dry silica (4 mL) is added     to the mixture and the solvent removed under vaccuum. The dry silica     is poured on the top of a flash silica gel column which is     subsequently eluted with EtOAc:MeOH (1:0Ø4:1) to give a pale orange     solid. ESI MS: m/z (rel intensity) 384 (M⁺+H, 100), 406 (M⁺+Na, 82),     422 (M⁺+K, 65).

Example 63

-   a,     (1N)-4-n-Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1-piperidyl-pyrrolidine:     The starting amine 43c (1.06 g, 1.88 mmole) is taken in 10 mL of DMF     and 1.5 mL of NEt₃ and treated with 2 mL of 2-bromoethyl ether. The     resulting mixture is then heated to 60° C. for 16 hr and partitioned     between dil Na₂CO₃ and EtOAc. The organic layer is then dried over     MgSO₄, filtered and evaparated. The crude residue was     chromatographed over flash silica with Hexane:EtoAc (1:1 to 0:1) to     give the title compound as a clear oil. ESI MS: m/z (rel intensity)     425 (M⁺+H). -   b.     (1N)-4-n-Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1-piperidyl-pyrrolidine:     The starting methylester. 63a (851 mg, 2.01 mmole) is taken in 1 mL     of methanol, treated with NH₂OK (0.381 mL, 0.86 M in methanol,     solution prepared as described in Fieser and Fieser, Vol 1, p 478)     and stirred overnight. The following morning, dry silica (2 mL) is     added to the mixture and the solvent removed under vaccuum. The dry     silica is poured on the top of a flash silica gel column which is     subsequently eluted with EtOAc:MeOH (1:0Ø9:1) to give 543 mg (64%)     of a pale orange solid. This was recrystallized from hexane:EtOAc to     give pale orange solid. ESI MS: m/z (rel intensity) 426.1 (M⁺+H).

Example 64

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-morpholinopyrrolidine:     The starting amine 42b (590 mg, 1.88 mmole) is taken in 4 mL of DMF     and 1 mL of NEt₃ and treated with 1 mL of 2-bromoethyl ether. The     resulting mixture is then heated to 60° C. for 3 hr and partitioned     between dil NaCO₃ and EtOAc. The organic layer is then dried over     MgSO₄, filtered and evaparated. The crude residue was     chromatographed over flash silica with EtOAc:MeOH (9:1) to give the     title compound as a white solid. ESI MS: m/z (rel intensity) 385.1     (M⁺+H). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-morpholinopyrrolidine:     The starting methylester 64a (310 mg, 0.86 mmole) is treated with     NH₂OK (2 mL, 1.25 M in methalol) in 4 mL mL of methanol as described     for 63b to give material which is puffed to a white solid under     vacuum and not recrystallized. ESI MS: m/z (rel intensity) 386.1     (M⁺+H, 100), 565.1 (12), 424.0 (15), 408.1 (M+NH₄ ⁺, 7), 218.1 (20),     202.1 (13).

Example 65

-   a.     (1N)-4-n-Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-morpholinopyrrolidine:     The starting amine 43c (7.2 g, 20.2 mmole), was taken in 5.0 mL of     DMF and 15 mL of Et₃N with 2-bromoethyl ether and converted to the     title compound as described for compound 63a. ESI MS: m/z (rel     intensity) 427.18 (M⁺+H). -   b.     (1N)-4-n-Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-morpholinopyrrolidine:     The starting methylester 65a (6.5 g, 15.2 mmole) is treated with     NH₂OK (24 mL, 1.25 M in methalol) in 20 mL mL of methanol as     described for 63b to give material which is puffed to a white solid     under vacuum and not recrystallized. ESI MS: m/z (rel intensity)     428.08 (M⁺H, 100), 450.07 (M⁺+Na, 8), 465.99 (M⁺+K, 15).

Example 66

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(4,4-dioxythio-morpholino)-pyrrolidine:     The starting amine 42b (560 mg, 1.79 mmole), was taken in 10 mL of     DMF and 1 mL of N-methylmorpholine with di-2-bromoethylsulfone (500     mg, 1.79 mmole) and converted to the title compound as described for     compound 63a. ESI MS: m/z (rel intensity) 433.1 (M⁺+H). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(4,4-dioxy-thiomorpholino)-pyrrolidine:     The starting methyl ester 66a (420 mg, 976 mmole) was converted to     the title compound as described for compound 63b. This material was     then recrystallized from EtOAC:methanol to give first crop crystalls     and second crop crystalls. ESI MS: m/z (rel intensity) 434.0 (M⁺+H,     100), 456.0 (M⁺+Na, 32).

Example 67

-   a.     (N)-4-n-Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(4,4-dioxythio-morpholino)-pyrrolidine:     The starting amine 43c (1.00 g, 2.81 mmole), was taken in 5 mL of     DMF and 2 mL of N-methylmorpholine with di-2-bromoethylsulfone (750     mg, 2.68 mmole) and converted to the title compound as described for     compound 63a. ESI MS: m/z (rel intensity) 475.0 (M⁺+H)

b. (1N)-4-n-Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(4,4-dioxythiomorpholino)-pyrrolidine: The starting methylester 67a (1.01 g, 2.83 mmole) is treated with NH₂OK (4 mL, 1.25 M in methalol) in 4 mL of methanol as described for 63b to give material which is puffed to a white solid under vacuum and not recrystallized. ESI MS: m/z (rel intensity) 476.1 (M⁺+H, 100), 498.1 (M⁺+Na, 22).

Example X Q R P 68 OMe Me H H 69 OnBu Me H H 70 OMe CH₂CH═CH₃ H H 71 OnBu H CH₃ CH₃ 72 OnBu H H CH₃ 73 O(CH₂)₂OMe CH₃ H H 74 OPh CH₃ H H 75 OCH(CH₃)₂ CH₃ H H

Example 68

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1N-(3N-methylhydantoyl)-pyrroildine:     Diethylazodicarboxylate (1.8 mL, 11.42 mmole) is added to a stirred     solution of the starting alcohol 1a (3.0 g, 9.51 mmole),     triphenylphosphene (3.74 g, 9.51 mmole), and 1-methylhydantoin (1.3     g, 11.42 mmole) in 30 mL of CH₂Cl₂ and stirred for 16 hrs at rt. The     mixture is then chromatographed over flash silica with hexane and     then hexane:EtOAc (1:1) to give colorless glass which is     recrystallized from methanol to give a white powder. ESI MS: m/z     (rel intensity) 412.1 (M⁺+H, 100), 429.1 (M⁺+NH₃, 45). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1N-(3N-methylhydantoyl)-pyrrolidine:     The starting methyl ester 68a (500 mg, 1.22 mmole) is taken in 7 mL     of methanol/tetrahydrofuran (1:1), and treated with NH₂OK (2.5 ml,     1.25M in methanol) and stirred overnight. The following morning, dry     silica (1.5 mL) is added to the mixture and the solvent removed     under vacuum. The dry silica is poured on top of a flash silica     column which is subsequently eluted with ethyl acetate followed with     ethyl:acetate (9:1) to give a clear glass which is puffed to a foamy     solid by slight heating under vacuum. The product is recrystallized     from cold methanol to give a white powder. ESI MS: m/z (rel     intensity) 413.0 (M⁺+H, 100), 430.0(M⁺+NH₃, 55).

Example 69

-   a.     (1N)-4-n-Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1-(3N-methyl-hydantoyl)-pyrrolidine:     Diethylazodicarboxylate (1.6 mL, 10.24 mmole) is added to a stirred     solution of the starting alcohol 29a (3.05 g, 8.53 mmole),     triphenylphosphine (3.36 g, 12.80 mmole), and 1-methyl-hydantoin     (1.17 mg, 10.24 mmole) in 60 mL of CH₂Cl₂ and stirred for 16 hrs at     rt. The mixture is then chromatographed over silica with hexane     followed by hexane:EtOAc (1:1) and finally with EtOAc to give a     colorless gum. The product was recrystallized from EtOAc-hexane to     give a white powder. ESI MS: m/z (rel intensity) 454.05 (M⁺+H, 100),     471.05 (M⁺+NH₃, 30). -   b.     (1N)-4-n-butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1N-(3N-methylhydantoyl)-pyrrolidine:     The starting methyl ester 69a (500 mg, 1.22 mmole) is taken in 7 mL     of methanol/tetrahydrofuran (1:1), and treated with NH₂OK (2.5 ml,     1.25 M in methanol) and stirred overnight. The following morning,     dry silica (1.5 ml) is added to the mixture and the solvent removed     under vacuum. The dry silica is poured on top of a flash silica     column which is subsequently eluted with ethyl acetate followed with     ethyl acetate:methanol (9:1) to give a clear glass which is puffed     to a foamy solid by slight heating under vacuum. The product is     recrystallized from cold methanol to give a white powder. ESI MS:     m/z (rel intensity) 455.0 (M⁺+H, 100), 472.0 (M⁺+NH₃, 50).

Example 70

-   a.     (1N)-4-n-butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1N-(3N-allylhydantoyl)-pyrrolidine:     Diethylazodicarboxylate (1.1 mL, 6.98 mmole) is added to a stirred     solution of the starting alcohol 1a (2.08 g, 5.82 mmole),     triphenylphosphine (2.29 g, 8.73 mmole), and 1-allylhydantoin (979     mg, 6.98 mmole) in 40 mL of CH₂Cl₂ and stirred for 16 hrs at rt. The     mixture is then chromatographed over silica with hexane:EtOAc (8:2)     followed by hexane:EtOAc (1:1) to give a colorless gum. ESI MS: m/z     (rel intensity) 480.0 (M⁺+H, 100), 497.0(M⁺+NH₃, 20). -   b.     (1N)-4-n-butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1N-(3N-allylhydantoyl)-pyrrolidine:     The starting methyl ester 70a (549 mg, 1.15 mmole) is taken in 2 mL     of methanol/tetrahydrofuran (1:1), and treated with NH₂OK (1.5 mL,     1.25 M in methanol) and stirred overnight. The following morning,     dry silica (1.5 mL) is added to the mixture and the solvent removed     under vacuum. The dry silica is poured on top of a flash silica     column which is subsequently eluted with ethyl acetate followed with     ethyl acetate:methanol (8:2) to give a clear glass whic is purified     to a foamy solid by slight heating under vacuum. The product was     recrystallized from cold methanol to give a of white powder. ESI MS:     m/z (rel intensity) 481.2 (M⁺+H, 100), 498.2(M⁺+NH₃, 60).

Example 71

-   a.     (1N)-4-n-butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1N-(4-dimethylhydantoyl)-pyrrolidine:     Diethylazodicarboxylate (0.530 mL, 3.36 mmole) is added to a stirred     solution of the starting alcohol 29a (1.00 g, 2.80 mmole),     triphenylphosphine (1.10 g, 4.20 mmole), and 5,5-dimethylhydantoin     (430 mg, 3.36 mmole) in 20 mL of CH₂Cl₂ and stirred for 16 hrs at     rt. The mixture is then chromatographed over silica with     hexane:EtOAc (8:2) followed by hexane:EtOAc (1:1) to give a     colorless gum. ESI MS: m/z (rel intensity) 468.1 (M⁺+H, 100),     485.1(M⁺+NH₃, 30). -   b.     (1N)-4-n-butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1N-(4-dimethylhydantoyl)-pyrrolidine:     The starting methyl ester 71a (754 mg, 1.61 mmole) is taken in 2 mL     of methanol/tetrahydrofuran (1:1), and treated with NH₂OK (2.0 mL,     1.25M in methanol) and stirred overnight. The following morning, dry     silica (1.5 mL) is added to the mixture and the solvent removed     under vacuum. The dry silica is poured on top of a flash silica     column which is subsequently eluted with hexane:ethyl acetate (1:1)     followed with hexane:ethyl acetate (2:8) and finally with ethyl     acetate:methanol (8:2) to give a clear glass which is puffed to a     foamy solid by slight heating under vacuum. The product is     recrystallized from cold methanol to give the title compound as a     white powder. ESI MS: m/z (rel intensity) 469.0 (M⁺+H, 100), 486.0     (M⁺+NH₃, 10).

Example 72

-   a.     (1N)-4-n-butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1N-(4S-methyl-hydantoyl)-pyrrolidine:     Diethylazodicarboxylate (0.530 mL, 3.36 mmole) is added to a stirred     solution of the starting alcohol 29a (1.00 g, 2.80 mmole),     triphenylphosphine (1.10 g, 4.20 mmole), and (L)-5-methylhydantoin     (383 mg, 3.36 mmole) in 20 mL of CH₂Cl₂ and stirred for 16 hrs at     rt. The mixture is then chromatographed over silica with     hexane:EtOAc (8:2) followed by hexane:EtOAc (1:1) to give a     colorless gum. This is then repurified over a second column eluting     first with hexane:EtAcO (1:1) followed by EtOAc:hexane (8:2). 1H NMR     showes a mitsunobu impurity (20%) remaining after two column     purifications and the material is carried forwared to the next step     without further purification. ESI MS: m/z (rel intensity) 454.0     (M⁺+H, 100), 471.0 (M⁺+NH₃, 20). -   b.     (1N)-4-n-butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1N-(4S-methyl-hydantoyl)-pyrrolidine:     The starting methyl ester 72a (497 mg, 1.10 mmole) is taken in 2 mL     of methanol/tetrahydrofuran (1:1), and treated with NH₂OK (1.5 mL,     1.25M in methanol) and stirred overnight. The following morning, dry     silica (1.5 mL) is added to the mixture and the solvent removed     under vacuum. The dry silica is poured on top of a flash silica     column which is subsequently eluted with ethyl acetate followed with     ethyl acetate:methanol (9:1) to give a clear glass which is puffed     to a foamy solid by slight heating under vacuum. The product is     recrystallized from cold methanol to give the title compound as a of     white powder. ESI MS: m/z (rel intensity) 455.0 (M⁺+H, 100), 472.0     (M⁺+NH₃, 30).

Example 73

-   a.     (1N)-4-(2-methoxyethoxy)-phenylsulfonyl-(2R)-carbomethoxy-(4S)-1N-(3N-methylhydantoyl)-pyrrolidine:     Diethylazodicarboxylate (0.546 mL, 3.47 mmole) is added to a stirred     solution of the starting alcohol 34b (1.04 g, 2.89 mmole),     triphenylphosphine (1.14 g, 4.34 mmole), and 1-methylhydantoin (396     mg, 3.47 mmole) in 20 mL of CH₂Cl₂ and stirred for 16 hrs at rt. The     mixture is then chromatographed over silica with hexane:EtOAc (1:1)     followed by hexane:EtOAc (2:8) to give a colorless gum. ESI MS: m/z     (rel intensity) 456.14 (M⁺+H, 100), 473.15 (M⁺+NH₃, 10). -   b.     (1N)-4-(2-methoxyethoxy)-phenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1N-(3N-methylhydantoyl)-pyrrolidine:     The starting methyl ester 73a (725 mg, 1.59 mmole) is taken in 2 mL     of methanol/tetrahydrofuran (1:1), and treated with NH₂OK (2 mL,     1.25 M in methanol) and stirred overnight. The following morning,     dry silica (1.5 mL) is added to the mixture and the solvent removed     under vacuum. The dry silica is poured on top of a flash silica     column which is subsequently eluted with ethyl acetate followed with     ethyl acetate:methanol (8:2) to give a clear glass which is purffed     to a foamy solid by slight heating under vacuum. The product was     recrystallized from cold methanol to give the tide compound as a     white powder. ESI MS: m/z (rel intensity) 457.08 (M⁺+H, 100), 474.09     (M⁺+NH₃, 60).

Example 74

-   a.     (1N)-4-phenoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1N-(3N-methylhydantoyl)-pyrrolidine:     Diethylazodicarboxylate (0.570 mL, 3.62 mmole) is added to a stirred     solution of the starting alcohol 35b (1.14 g, 3.02 mmole),     triphenylphosphine (1.19 g, 4.53 mmole), and 1-methyl-hydantoin (413     mg, 3.62 mmole) in 20 mL of CH₂Cl₂ and stirred for 16 hrs at rt. The     mixture is then chromatographed over silica with hexane:EtOAc (8:2)     followed by hexane:EtOAc (1:1) with product eluting with     Hexane:EtOAc (2:8) to give a colorless gum. ESI MS: m/z (rel     intensity) 474.03 (M⁺+H. 100), 491.03 (M⁺+NH₃, 20). -   b.     (1N)-4-phenoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1N-(3N-methylhydantoyl)-pyrrolidine:     The starting methyl ester (1.50 g, 1.59 mmole) is taken in 10 mL of     methanol/tetrahydrofuran (1:1), and treated with NH₂OK (5 mL, 1.25M     in methanol) and stirred overnight. The following morning, dry     silica (5 mL) is added to the mixture and the solvent removed under     vacuum. The dry silica is poured on top of a flash silica column     which is subsequently eluted with ethyl acetate:hexane (1:1), then     ethyl acetate followed with ethyl acetate:methanol (8:2) to give a     clear glass which is puffed to a foamy solid by slight heating under     vacuum. The product is recrystallized from cold methanol to give the     title compound as a white powder. ESI MS: m/z (rel intensity) 475.09     (M⁺+H, 100), 497.07 (M⁺+NH₃, 60).

Example 75

-   a.     (±)-(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-5-pyrrolidinone:     The 2-carboxy-β-lactam starting material (10 g, 77.5 mmoles) is     dissolved in 200 ml of methanol at 0° C. followed by the addition of     0.76M diazomethane until the color of the reaction miture remained     yellow. The reaction is then stirred for an additional 30 minutes.     This is evaporated down to get rid of excess methanol and     diazomethane. The yield is quantitative and the product is carried     forward without further purification. The methyl ester produced     above (11.08 g, 77.5 mmoles) is dissolved in 500 mL of dry THF at     0° C. followed by the one portion addition of t-butoxide (9.15 g,     77.5 mmoles) and stirred for 1 hour. Next, 4-methoxybenzene sulfonyl     chloride (19.2 g, 93.0 mmoles) is added and this stirred over night.     The reaction is quenched with saturated sodium bicarbonate until     basic and extracted with ether 3 times. The ether layer is washed     with 1N HCl, sodium bicarbonate, and ammonium chloride, dried over     magnesium sulfate and evapoated done. Chromotography is performed on     silica gel using a solvent system of ethyl acetate:hexane (1:1) to     give the title compound. CI⁺ MS: m/z (rel intensity) 314.0 (M⁺+H,     100). -   b. (±)-(1N)-4-Methoxyphenylsulfonyl-(2R)-carboxyl-5-pyrrolidinone:     The sulfonated methyl ester 75a (8.5 g, 27.12 mmoles) is dissolved     in 60 mL of a THF and methanol (3:1). Lithium hydroxide (2.27 g,     94.9 mmoles) is then added in THF and methanol (3:1). An additional     10 ml of methanol is added to the reaction mixture to improve     solubility. The reaction stirred for 3 hours. The reaction is     quenched with water and then evaporated down to get rid of the     organic solvents. The water layer is extracted one time with ether.     Then the water layer is acidified to pH=2 and this is extracted with     ethyl acetate 3 times and washed with sodium chloride and dried over     magnesium sulfate. This is evaporated down to give give the tide     compound. CI⁺ MS: m/z (rel intensity) 300.0 (M⁺+H, 100). -   c.     (±)-(1N)-4-Methoxyphenylsulfonyl-(2R)-O-benzyl-N-hydroxycarboxamido-5-pyrrolidinone:     The carboxylic acid 75b (1.0 g, 3.3 mmoles) is dissolved in 15 mL of     DMF at 0C followed by the addition of triethyl amine (1.37 mL, 9.9     mmoles), 4-methylmorpholine N-oxide (1.08 g, 9.9 mmoles),     1-hydroxy-benzotriazole (1.33 g, 9.9 mmoles), and     1-ethyl-3(3-dimethyl-aminopropyl)carbodiimide (0.76 g, 4.01 mmoles).     This stirred for 30 minutes followed by the addition of the     benzylamine (0.64 g, 4.01 mmoles). The reaction stirred overnight.     The reaction is quencehed with saturated sodium bicarbonate and then     extracted with ethyl acetate 3 times, washed with 1NHCl and sodium     chloride, dried over magnesium sulfate and evaporated down.     Chromotography is run on silica gel using ethyl acetate and     methylene chloride (5:1) to give give the title compound. CI⁺ MS:     m/z (rel intensity) 404.0 (M⁺+H, 100). -   d.     (±)-(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-5-pyrrolidinone:     The benzyl protected lactam 75c (0.42 g, 1.04 mmoles) is dissolved     in 20 mL of ethyl acetate followed by the addition of palladium on     activated carbon (wet) (0.042 g, [10% of weight]). The reaction     flask is degassed of all oxygen and then put under hydogen balloon     pressure for overnight. After the flask is degassed of hydrogen, the     palladium is filtered off through cellite and the ethyl acetate is     rotovapped off. The compound is recrystallized with ethyl acetate     and hexane to give the title compound. ESI MS: m/z (rel intensity)     314.0 (M⁺+H, 100).

Example 76

-   a.     (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-4,4-dithiolethyl-pyrrolidine:     The ketone 25a (1.5 g, 4.79 mmol) is dissolved in 30 mL of anhydrous     dichloromethane and then ethanethiol (0.53 mL, 7.18 mmol) and borane     trifluoride etherate (0.24 mL, 1.91 mmol) is added. The resulting     mixture is stirred at room temperature for 14 h. The reaction     mixture is quenched by the the addition of 1N sodium hydroxide and     then extracted 3 times with ethyl acetate. The organic layers are     washed with water and saturated ammonium chloride solution, dried     (MgSO₄), filtered and concentrated under reduced pressure to give     the title compound. CI⁺ MS: m/z 420 (M⁺+H)). -   b.     (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-4,4-dithiolethylpyrrolidine:     The thioketal 76a (0.32 g, 0.89 mmol) is added to a 1.5 M solution     of potassium hydroxylamine solution (4.0 mL, prepared as described     in Fieser and Fieser, Vol. 1, p. 478.). The reaction mixture is     stirred overnight and then acidified with 1N HCl. The resulting     mixture is then extracted 3 times with ethyl acetate, dried (MgSO₄),     filtered and concentrated under reduced pressure. Chromotography was     performed on silica gel using EtOAc:hexane:formic acid (1:1:0.1) as     the eluent to give the title compound. ESI MS: m/z 421 (M⁺+H), 443     (M⁺+Na).

Examples 77-180

The following compounds are made using the methods described and exemplified above. In these Examples R₁ is HONH, Z and W are hydrogen, and Y and Ar substitution, as well as ring size are described in the chart below. Hence, a simplified diagram of the molecule exemplified is:

Y Ar n Example 78 —OH 4-NO₂—C₆H₄— 1 Example 79 —OH 4-i-BuO—C₆H₄— 1 Example 80 —OH 4-(C₆H₅)O—C₆H₄— 1 Example 81 —OH 4-(4-F—C₆H₄)O—C₆H₄— 1 Example 82 —OH 4-(4-Cl—C₆H₄)O—C₆H₄— 1 Example 83 —OH 4-(4-Br—C₆H₄)O—C₆H₄— 1 Example 84 —OH 4-(4-Me—C₆H₄)O—C₆H₄— 1 Example 85 —OH 4-(4-MeO—C₆H₄)O—C₆H₄— 1 Example 86 —OH 4-(4-CN—C₆H₄)O—C₆H₄— 1 Example 87 —OH 4-(4-Me₂N—C₆H₄)O—C₆H₄— 1 Example 88 —OH 4-EtO—C₆H₄— 1 Example 89 —OH 4-i-PrO—C₆H₄— 1 Example 90 —OH 4-n-PrO—C₆H₄— 1 Example 91 —OH 4-Br—C₆H₄— 1 Example 92 —OH 4-C₆H₅—C₆H₄— 1 Example 93 —OH 4-(4-F—C₆H₅)—C₆H₄— 1 Example 94 —OH 4-(4-Cl—C₆H₅)—C₆H₄— 1 Example 95 —OH 4-(4-Br—C₆H₅)—C₆H₄— 1 Example 96 —OH 4-(4-Me₂N—C₆H₄)—C₆H₄— 1 Example 97 —OH 4-(4-CN—C₆H₄)—C₆H₄— 1 Example 98 —OH 4-(4-MeO—C₆H₄)—C₆H₄— 1 Example 99 —OH 4-(4-C₅H₄N)O—C₆H₄— 1 Example 100 —OH 4-(3-C₅H₄N)O—C₆H₄— 1 Example 101 —OH 4-(2-C₅H₄N)O—C₆H₄— 1 Example 102 —OH C₆H₅CH₂CH₂— 1 Example 103 —OH C₆H₅CH₂— 1 Example 104 —OH (4-C₅H₄N)CH₂CH₂— 1 Example 105 —OH (2-C₅H₄N)CH₂CH₂— 1 Example 106 —OH 4-(C₆H₁₁)O—C₆H₄— 1 Example 107 —OH 4-(C₅H₁₁)O—C₆H₄— 1 Example 108 —OH 4-(C₆H₁₃)O—C₆H₄— 1 Example 109 —OH 4-(CH₃OCH₂CH₂)O—C₆H₄— 1 Example 110 —OH 5-(2-pyridinyl)-2-thienyl- 1 Example 111 —OH 5-(3-isoxazolyl)-2-thienyl- 1 Example 112 —OH 5-(2-(methylthio)pyrimidin-4- 1 yl)-2-thienyl- Example 113 —OH 5-(3-(1-methyl-5- (trifluoromethyl)pyrazolyl)-2- 1 thienyl Example 114 —NHP(O)(CH₃)C₆H₅ CH₃CH₂CH₂OC₆H₄— 1 Example 115 —NHCOCH₂C₆H₅ CH₃CH₂CH₂OC₆H₄— 1 Example 116 —NHCO(2-pyridyl) CH₃CH₂CH₂OC₆H₄— 1 Example 117 —NHCOCH₂NMe₂ CH₃CH₂CH₂OC₆H₄— 1 Example 118 —NHCO-2-(1-methyl)-imidazyl CH₃CH₂CH₂OC₆H₄— 1 Example 119 —NHSO₂CH₃ 4-(4-C₅H₄N)O—C₆H₄— 1 Example 120 —NHCOC₆H₅ CH₃CH₂CH₂OC₆H₄— 1 Example 121 —NMe₂ CH₃CH₂CH₂OC₆H₄— 1 Example 122 —N(CH₂CH₃)₂ CH₃CH₂CH₂OC₆H₄— 1 Example 123 —NMe₂ 4-(4-C₅H₄N)O—C₆H₄— 1 Example 124 —N(CH₂CH₃)₂ 4-(4-C₅H₄N)O—C₆H₄— 1 Example 125 —N(CH₂CH₃)SO₂CH₃ CH₃CH₂CH₂OC₆H₄— 1 Example 126 —N(CH₂CH₃)COCH₃ CH₃CH₂CH₂OC₆H₄— 1 Example 127 —N(CH₂CH₃)SO₂CH₃ 4-(4-C₅H₄N)O—C₆H₄— 1 Example 128 —N(CH₂CH₃)COCH₃ 4-(4-C₅H₄N)O—C₆H₄— 1 Example 129 —N(CH₃)CO(2-pyridyl) CH₃CH₂CH₂OC₆H₄— 1 Example 130 —N(CH₃)CO(4-pyridyl) CH₃CH₂CH₂OC₆H₄— 1 Example 131 —N(CH₃)COC₆H₅ CH₃CH₂CH₂OC₆H₄— 1 Example 132 —N(CH₃)CO-1N-methylpiperazine CH₃CH₂CH₂OC₆H₄— 1 Example 133 —N(CH₃)COH CH₃CH₂CH₂OC₆H₄— 1 Example 134 —N(CH₃)COCH₂OCH₃ CH₃CH₂CH₂OC₆H₄— 1 Example 135 —N(CH₃)COCH(CH₃)₂ CH₃CH₂CH₂OC₆H₄— 1 Example 136 —N(CH₃)CO(furanyl) CH₃CH₂CH₂OC₆H₄— 1 Example 137 —N(CH₃)CO(oxazolinyl) CH₃CH₂CH₂OC₆H₄— 1 Example 138 —N(CH₃)COCH₂CN CH₃CH₂CH₂OC₆H₄— 1 Example 139 —N(CH₃)CO(CH2)N(CH₃)₂ CH₃CH₂CH₂OC₆H₄— 1 Example 140 —N(CH₃)SO₂-3-(1N-methylimidazyl) CH₃CH₂CH₂OC₆H₄— 1 Example 141 —N(CH₃)SO₂CH(CH₃)₂ CH₃CH₂CH₂OC₆H₄— 1 Example 142 —CH₂NHSO₂CH₃ CH₃OC₆H₄— 1 Example 143 —CH₂NHSO₂C₅H₅ CH₃OC₆H₄— 1 Example 144 —CH₂NHCOCH₆H₅ CH₃OC₆H₄— 1 Example 145 —CH₂NHCOCH₂CH₂CH₃ CH₃OC₆H₄— 1 Example 146 —CH₂N(CH₃)COCH₃ CH₃OC₆H₄— 1 Example 147 —CH₂N(CH₃)SO₂C₆H₅OMe CH₃OC₆H₄— 1 Example 148 —CH₂N(CH₂C₆H₅)SO₂CH₃ CH₃OC₆H₄— 1 Example 149 —OH CH₃OC₆H₄— 2 Example 150 —S—C₆H₅ CH₃OC₆H₄— 2 Example 151 —(OMe)₂ CH₃OC₆H₄— 2 Example 152 —OH BrC₆H₄— 2 Example 153 -3-methyl-1-hydantoyl— 4-EtO-C₆H₄— 1 Example 154 -3-methyl-1-hydantoyl— 4-i-PrO-C₆H₄— 1 Example 155 -3-methyl-1-hydantoyl— 5-(2-pyridinyl)-2-thienyl— 1 Example 156 -3-methyl-1-hydantoyl— 4-Br—C₆H₄— 1 Example 157 -3-methyl-1-hydantoyl— 2-Me-4-Br—C₆H₄— 1 Example 158 -3-methyl-1-hydantoyl— 4-(C₆H₅)O—C₆H₄— 1 Example 159 -3-methyl-1-hydantoyl— 4-(4-F—C₆H₄)O—C₆H₄— 1 Example 160 -3-methyl-1-hydantoyl— (4-C₅H₄N)CH₂CH₂— 1 Example 161 -3-methyl-1-hydantoyl— 4-(4-C₅H₄N)O—C₆H₄— 1 Example 162 -1N-morpholino 4-EtO—C₆H₄— 1 Example 163 -1N-morpholino 4-i-PrO—C₆H₄— 1 Example 164 -1N-morpholino 5-(2-pyridinyl)-2-thienyl— 1 Example 165 -1N-morpholino 4-Br—C₆H₄— 1 Example 166 -1N-morpholino 2-Me-4-Br—C₆H₄— 1 Example 167 -1N-morpholino 4-(C₆H₅)O—C₆H₄— 1 Example 168 -1N-morpholino 4-(4-F-C₆H₄)O—C₆H₄— 1 Example 169 -1N-morpholino (4-C₅H₄N)CH₂CH₂— 1 Example 170 -1N-morpholino 4-(4-C₅H₄N)O—C₆H₄— 1 Example 171 -1N-valerolactamyl- (4-C₅H₄N)OC₆H₄— 1 Example 172 -1N-valerolactamyl- 4-n-BuOC₆H₄— 1 Example 173 —(OMe)₂ CH₃CH₂OC₆H₄— 1 Example 174 —(OMe)₂ CH₃CN₂CH₂OC₆H₄— 1 Example 175 —(OMe)₂ 4-(4-C₅H₄N)O—C₆H₄— 1 Example 176 —(OCH₂CH₃)₂ CH₃CH₂OC₆H₄— 1 Example 177 —(OCH₂CH₃)₂ CH₃CN₂CH₂OC₆H₄— 1 Example 178 —(OCH₂CH₃)₂ 4-(4-C₅H₄N)O—C₆H₄— 1 Example 179 —(OCH₂CH₂OCH₃) CH₃CH₂OC₆H₄— 1 Example 180 —(OCH₂CH₂OCH₃) CH₃CN₂CH₂OC₆H₄— 1 Example 181 —(OCH₂CH₂OCH₃) 4-(4-C₅H₄N)O—C₆H₄— 1 Examples 78-113 are prepared analogously to Example 1 using the appropriately functionalized sulfonyl chloride. The sulfonyl chlorides which are used to prepare the above examples are either purchased from commericial sources or prepared via known methods. For example, the 4-phenoxyphenylsulfonyl chloride used for the preparation of Example 17, was prepared as described by R. J. Cremlyn et al in Aust. J. Chem., 1979, 32, 445.52. Examples 114-120 are prepared using methods described in examples 42-61 using the appropriate alkyl, acyl, sulfonyl, phosphinyl or isocyanate derivative. Examples 129-141 are prepared by first mono-methylating the appropriate primary amine derivative as described by S. Krishnamurthy et al in Tetrahedron Lett. 1983, 23 (33), 3315, and then adding adding the appropriate alkyl, acyl, sulfonyl, phosphinyl or isocyanate derivative as described in examples 42-61. Examples 142-148 are prepared from cyanide addition into mesylate 15a followed by reduction to the corresponding free amine and treatment with the appropriate alkyl, acyl, sulfonyl, or phosphinyl derivative. Examples 149-152 are prepared by ketalization or reduction and/or nucleophillic substitution of the appropriately functionalized 4-ketopipecolic acid described by J.-P. Obrecht et al in Organic Synthesis 1992, 200. Examples 153-161 are prepared as described for example 68. Examples 162-170 are prepared as described for example 65. Examples 171-172 are prepared by acylation of a primary amine of type 43c with 5-bromovaleryl chloride followed base promoted ring closure and hydroxamic acid formation. Examples 173-181 are prepared by standard ketalization methods of ketones of type 25a.

These examples provide the skilled artisan with sufficient guidance as to making the present invention and do not limit it in any way.

Composition and Method of Use Examples

The compounds of the invention are useful to prepare compositions for the treatment of ailments and the like. The following composition and method examples do not limit the invention, but provide guidance to the skilled artisan to prepare and use the compounds, compositions and methods of the invention. In each case the compounds formula I may be substituted for the example compound shown below with similar results.

The methods of use exemplified do not limit the invention, but provide guidance to the skilled artisan to use the compounds, compositions and methods of the invention. The skilled practitioner will appreciate that the examples provide guidance and may be varied based on condition and the patient.

Example A

A tablet composition for oral administration, according to the present invention, is made comprising: Component Amount The compound of Example 9  15. mg Lactose 120. mg Maize Starch  70. mg Talc  4. mg Magnesium Stearate  1. mg (Other compounds having a structure according to Formula (I) are used with substantially similar results.)

A human female subject weighing 60 kg (132 lbs), suffering from rheumatoid arthritis, is treated by a method of this invention. Specifically, for 2 years, a regimen of three tablets per day is administered orally to said subject.

At the end of the treatment period, the patient is examined and is found to have reduced inflammation, and improved mobility without concomitant pain.

Example B

A capsule for oral administration, according to the present invention, is made comprising: Component Amount (% w/w) The compound of Example 3 15% Polyethylene glycol 85% (Other compounds having a structure according to Formula (I) are used with substantially similar results.)

A human male subject weighing 90 kg (198 lbs), suffering from osteoarthritis, is treated by a method of this invention. Specifically, for 5 years, a capsule containing 70 mg of the compound of Example 3 is administered daily to said subject.

At the end of the treatment period, the patient is examined via orthoscopy, and found to have no further advancement of erosion/fibrillation of the articular cartilage.

Example C

A saline-based composition for local administration, according to the present invention, is made comprising: Component Amount (% w/w) The compound of Example 13  5% Polyvinyl alcohol 15% Saline 80% (Other compounds having a structure according to Formula (I) are used with substantially similar results.)

A patient having deep corneal abrasion applies the drop to each eye twice a day. Healing is speeded, with no visual sequelae.

Example D

A topical composition for local administration, according to the present invention, is made comprising: Component Composition (% w/v) The compound of Example 3 0.20 Benzalkonium chloride 0.02 Thimerosal 0.002 d-Sorbitol 5.00 Glycine 0.35 Aromatics 0.075 Purified water q.s. Total = 100.00 (Other compounds having a structure according to Formula (1) are used with substantially similar results.)

A patient suffering from chemical burns applies the composition at each dressing change (b.i.d.). Scarring is substantially diminished.

Example E

A inhalation aerosol composition, according to the present invention, is made comprising: Component Composition (% w/v) Compound of Example 2 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 Sodium Saccharin 0.2 Propellant (F12, F114) q.s. Total = 100.0 (Other compounds having a structure according to Formula (1) are used with substantially similar results.)

An asthma sufferer sprays 0.01 mL via a pump actuator into the mouth while inhaling. Asthma symptoms are diminished.

Example F

A topical opthalmic composition, according to the present invention, is made comprising:

Component Composition (% w/v) Component Composition (% w/v) Compound of Example 5 0.10 Benzalkonium chloride 0.01 EDTA 0.05 Hydroxyethylcellulose (NATROSOL M) 0.50 Sodium metabisulfite 0.10 Sodium chloride (0.9%) q.s. Total = 100.0 (Other compounds having a structure according to Formula (I) are used with substantially similar results.)

A human male subject weighing 90 kg (198 lbs), suffering from corneal ulcerations, is treated by a method of this invention. Specifically, for 2 months, a saline solution containing 10 mg of the compound of Example 5 is administered to said subject's affected eye twice-daily.

Example G

A composition for parenteral administration is made comprising: Component Amount The compound of Example 4 100 mg/ml carrier Carrier: sodium citrate buffer with (percent by weight of carrier): lecithin 0.48% carboxymethylcellulose 0.53 povidone 0.50 methyl paraben 0.11 propyl paraben 0.011

The above ingredients are mixed, forming a suspension. Approximately 2.0 ml of the suspension is administered, via injection, to a human subject with a premetastatic tumor. The injection site juxtaposes the tumor. This dosage is repeated twice daily, for approximately 30 days. After 30 days, symptoms of the disease subside, and dosage is gradually decreased to maintain the patient.

(Other compounds having a structure according to Formula I are used with substantially similar results.)

Example H

A mouthwash composition is prepared; Component % w/v The compound of Example 1 3.00 SDA 40 Alcohol 8.00 Flavor 0.08 Emulsifier 0.08 Sodium Fluoride 0.05 Glycerin 10.00 Sweetener 0.02 Benzoic acid 0.05 Sodium hydroxide 0.20 Dye 0.04 Water balance to 100%

A patient with gum disease uses 1 ml of the mouthwash thrice daily to prevent further oral degeneration.

(Other compounds having a structure according to Formula I are used with substantially similar results.)

Example I

A lozenge composition is prepared; Component % w/v The compound of Example 3 0.01 Sorbitol 17.50 Mannitol 17.50 Starch 13.60 Sweetener 1.20 Flavor 11.70 Color 0.10 Corn Syrup balance to 100%

A patient uses the losenge to prevent loosening of an implant in the maxilla. (Other compounds having a structure according to Formula I are used with substantially similar results.)

Example J

Chewing Gum Composition Component w/v % The compound of Example 1 0.03 Sorbitol crystals 38.44 Paloja-T gum base* 20.00 Sorbitol (70% aqueous solution) 22.00 Mannitol 10.00 Glycerine 7.56 Flavor 1.00

A patient chews the gum to prevent loosening of dentures.

(Other compounds having a structure according to Formula I are used with substantially similar results.)

Example K

Components w/v % Compound of example 25 4.0 USP Water 50.656 Methylparaben 0.05 Propylparaben 0.01 Xanthan Gum 0.12 Guar Gum 0.09 Calcium carbonate 12.38 Antifoam 1.27 Sucrose 15.0 Sorbitol 11.0 Glycerin 5.0 Benzyl Alcohol 0.2 Citric Acid 0.15 Coolant 0.00888 Flavor 0.0645 Colorant 0.0014

The composition is prepared by first mixing 80 kg of gylcerin and all of the benzyl alcohol and heating to 65 C, then slowly adding and mixing together methylparaben, propylparaben, water, xanthan gum, and guar gum. Mix these ingredients for about 12 minutes with a Silverson in-line mixer. Then slowly add in the following ingredients in the following order: remaining glycerin, sorbitol, antifoam C, calcium carbonate, citric acid, and sucrose. Separately combine flavors and coolants and then slowly add to the other ingredients. Mix for about 40 minutes.

The patient takes the formulation to prevent flare up of colitis.

All references described herein are hereby incorporated by reference.

While particular embodiments of the subject invention have been described, it will be obvious to those skilled in the art that various changes and modifications of the subject invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention. 

1-8. (canceled)
 9. A method of preventing or treating a progressive ventricular dilation comprising administering to a mammal in need of such treatment, a safe and effective amount of a compound of having a structure according to Formula (I):

wherein: A is alkyl, heteroalkyl, aryl or heteroaryl, substituted or unsubstituted; R₁ is NHOR₂, where R₂ is hydrogen or alkyl; W is one or more of hydrogen, lower alkyl, or an alkylene bridge that forms a ring in addition to the ring depicted in Formula (I); Y is independently one or more of hydroxy, SR₃, SOR₄, SO₂R₈, alkoxy, or amino, wherein the amino is of formula NR₆,R₇, wherein R₆ and R₇ are independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, OR₃, SO₂R₈, COR₉, CSR₁₀, and PO(R₁₁)₂; R₃ is hydrogen, alkyl, aryl, or heteroaryl; R₄ is alkyl, aryl, or heteroaryl; each R₈ is independently chosen from group consisting of alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R₉ is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino or alkylarylamino; R₁₀ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino or alkylarylamino; R₁₁ is alkyl, aryl, heteroaryl, or heteroalkyl; Z is hydrogen, hydroxy, alkyl, or an alkylene or heteroalkylene bridge that forms a ring in addition to the ring depicted in Formula (I); and n is 1; provided that (i) when any one or more of R₃, R₄, R₈, R₉, R₁₀, R₁₁, W, Y or Z is itself, or together with another moiety forms, a heterocyclic moiety, that heterocyclic moiety is furan, and (ii) when W or Z is an alkylene or heteroalkylene bridge that forms a second ring fused to the ring depicted in Formula (I), that second ring does not include the ring carbon atom depicted in Formula (I) that is bonded to C(═O)—R₁; or an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.
 10. The method of claim 9, wherein the compound is of structure:

wherein: A is aryl or heteroaryl, substituted or unsubstituted; R₁ is NHOR₂, where R₂ is hydrogen or alkyl; W is one or more of hydrogen or lower alkyl; Y is independently one or more of hydroxy, SR₃, SOR₄, SO₂R₈, alkoxy, or amino, wherein the amino is of formula NR₆,R₇, wherein R₆ and R₇ are independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, OR₃, SO₂R₈, COR₉, CSR₁₀ and PO(R₁₁)₂; R₃ is hydrogen, alkyl, aryl, or heteroaryl; R₄ is alkyl, aryl, or heteroaryl; each R₈ is independently chosen from the group consisting of alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino; R₉ is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino or alkylarylamino; R₁₀ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino, or alkylarylamino; R₁₁ is alkyl, aryl, heteroaryl, or heteroalkyl; Z is hydrogen; and n is 1; or an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.
 11. The method of claim 10, wherein the compound is selected from the group consisting of: (1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-hydroxypyrrolidine; ((1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-hydroxypyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2S)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2S)-N-hydroxycarboxamido-(4S)-hydroxypyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-methoxypyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-(2-mercapto-benzothiazolyl)-pyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4R)-(2-mercaptobenzo-thiazolyl)-pyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-[(1N)-methyl-2-mercaptoimidazyl]-pyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4R)-[(1N)-methyl-2-mercaptoimidazyl]-pyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-phenoxypyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-(4-benzyloxy)-phenoxypyrrolidine; (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(3-N-phenylamino)-phenoxylpyrrolidine; (1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-phenoxypyrrolidine; (1N)-4-Methoxyphenylsulfonamido-(2R)-N-hydroxycarboxamido-(4S)-mercaptophenylpyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-(4-methoxyphenyl-thioloxy)-pyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-(3-methoxy-mercaptophenyl)-pyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-(nhexylamino)-pyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2R)-hydroxy carboxamido-(4S)-thiopyrrolidine; (±)-(1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(3S)-phenylpyrrolidine; (1N)-(4-Methylphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-hydroxypyrrolidine; (1N)-(3,4-Dimethoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine; (1N)-(2-Nitro-4-methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine; (1N)-4-^(n)Butoxyphenylsulfonamido-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine; (1N)-(4-^(n)Butoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-hydroxypyrrolidine; (1N)-(4-^(n)Butoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-(2-mercapto-benzothiazolyl)-pyrrolidine; (N)-(2-Nitro-4-methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-(2-mercapto-benzothiazolyl)-pyrrolidine; (1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-(4-methoxyphenyl-thioloxy)-pyrrolidine; (±)-(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-5-pyrrolidinone; (1N)-4-Methoxyphenylsulfonyl-(2R)-hydroxy-carboxamido-(4,4R)-hydroxy-ethylpyrrolidine; (1N)-4-Phenoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine; and (1N)-(4-^(n)Butoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-morpholinopyrrolidine.
 12. The method claim 11, wherein the compound is selected from the group consisting of: (1N)-4-Phenoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine; (1N)-4-^(n)Butoxyphenylsulfonamido-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine; (1N)-4-^(n)Butoxyphenysulfonyl)-2R)-N-hydroxycarboxamido-(4S)-hydroxypyrrolidine; and (1N)-(4-^(n)Butoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-morpholinopyrrolidine. 